Wnt/β-catenin signaling pathway: proteins' roles in osteoporosis and cancer diseases and the regulatory effects of natural compounds on osteoporosis.

Текст сохранён. Часть иллюстраций пока доступна только в первоисточнике; загрузка будет проверена повторно.

Introduction

Osteoporosis is a disease of the skeleton caused mainly by an imbalance in the number or function of osteoblasts and osteoclasts (Delany et al. 2000 ). Osteoporosis is characterized by decreased bone mass, reduced bone density and thinning of the bone, which makes the bones susceptible to injury and fracture and thus seriously affects the quality of life (Compston et al. 2019 ). Osteoblasts play an important role in the development of osteoporosis. When osteoporosis occurs, the production and activity of osteoblasts is severely affected, resulting in a decrease in the production or quality of new bone tissue. This causes bones to become weak and easily damaged, increasing the risk of fracture.

The main functions of osteoblasts include promoting bone formation, maintaining bone density and strength, repairing bone damage, and participating in the regulation of bone metabolism (Ponzetti and Rucci 2021 ). They help keep bones stable and healthy by continuously producing new bone tissue. In the treatment of osteoporosis, promoting the production and activity of osteoblasts can help increase bone density and reduce the risk of fractures, thus improving the symptoms of osteoporosis (Martínez-Reina et al. 2021 ). Therefore, understanding the differentiation process of osteoblasts is important for the prevention and treatment of osteoporosis.

Osteoblast differentiation is an extremely complex process, involving multiple signaling pathways and regulators such as BMP-Smad and Wnt/β-catenin signaling pathways (Yoshida et al. 2000 ; Hill et al. 2005 ). Among them, the Wnt/β-catenin signaling pathway is considered to be one of the most important and critical differentiation pathways, and abnormal activation or inhibition of the Wnt/β-catenin signaling pathway can lead to the development of bone-related diseases, such as osteoporosis and delayed fracture healing (Vlashi et al. 2023 ). Understanding osteoblast differentiation is crucial for the prevention and treatment of osteoporosis. The study of Wnt/β-catenin signaling pathway not only helps to understand the differentiation mechanism of osteoblasts, but also provides important clues for the treatment of related diseases and develops more effective prevention and treatment strategies. Drugs used to treat osteoporosis include those that inhibit bone resorption, those that promote bone formation, and anabolic drugs (Tonk et al. 2022 ).However, the associated adverse effects limit their usefulness in treating osteoporosis, and it is urgent to find new therapies for osteoporosis. Meanwhile, in recent years, studies have found that natural compounds have a regulatory effect on the Wnt/β-catenin signaling pathway, showing the ability to regulate bone morphogenesis by affecting the composition or activity of the Wnt/β-catenin signaling pathway. The Wnt/β-catenin signaling pathway is expected to become a therapeutic target. However, the mechanisms by which natural compounds regulate Wnt/β-catenin signaling are not fully understood. Further studies are needed to elucidate the detailed molecular mechanisms and to identify specific compounds with therapeutic potential. Although natural compounds have shown potential to modulate Wnt/β-catenin signaling in laboratory studies, there are still many challenges in translating them into clinical treatments, and natural compounds from different sources may have quality differences that affect the consistency of their therapeutic effects. In view of this, studying how natural compounds regulate the Wnt/β-catenin signaling pathway is not only an important part of understanding the mechanism of bone metabolism and also important for finding new treatments for osteoporosis.

Wnt/β-catenin signaling pathway

When there is no Wnt signaling or the Wnt receptor is blocked, the Axin-APC-GSK-3-CK1 complex will bind to free β-catenin in the cytoplasm and phosphorylate β-catenin, which will be degraded by the proteasome in the cytoplasm and therefore cannot enter the nucleus (Wiese et al. 2018 ; Nusse and Clevers 2017 ). Inside the nucleus, the LEF/TCF transcription factor family binds to the transcriptional repressor Groucho to form a complex protein structure that is unable to act on downstream target genes, leaving the cell surface in a relatively quiescent state(Routledge and Scholpp 2019 ).

In the presence of Wnt signaling, Wnt forms a complex with the Fzd receptor and the co-receptor LRP5/6 on the surface of the cell membrane, activating intracellular Dvl proteins and recruiting them to the cell membrane (Xue et al. 2024 ). The C-terminus of Fzd binds to and phosphorylates the PDZ and DEP regions of the Dvl protein, and the DIX of Dvl interacts with the DIX region of Axin to recruit Axin to the cell membrane, while the kinases GSK-3 and CK1, which bind to Axin, are also translocated to the membrane and phosphorylate the PPPSPxS site at the C-terminal end of LRP5/6, blocking the phosphorylation of β-catenin by GSK-3, and preventing the formation of the Axin-APC-GSK-3-CK1 complex (Bilic et al. 2007 ). As a result β-catenin cannot be degraded normally and accumulates abnormally in the cytoplasm. A large amount of free β-catenin enters the nucleus to disrupt the complex protein formed by the LEF/TCF family and the transcriptional repressor Groucho, and binds to transcription factors of the LEF/TCF family, while recruiting transcriptional cofactors to further activate the transcription factors, thus activating the expression of downstream target genes (Deldar Abad Paskeh et al. 2021 ) (Fig. 1 ). Fig. 1 The classic Wnt/β-catenin signaling pathway: mechanisms in closed and open states. A In the absence of Wnt ligands, the Wnt/β-catenin signaling pathway is in the off-state (OFF-State). At this time, a disruption complex consisting of GSK3β, Axin, APC, and CK1 phosphorylates β-catenin. The phosphorylated β-catenin is degraded by ubiquitination. In the nucleus, in the absence of β-catenin the LEF/TCF family of transcription factors binds to the transcriptional repressor Groucho and represses the expression of target genes. B Wnt /β-catenin signaling is active in the presence of Wnt ligand (ON-State), which binds to LRP5/6, Fed co-receptors, and subsequently recruits Axin, GSK3β, and Dvl, preventing the phosphorylation of β-catenin, and thus preventing the formation of the destruction complex. In the nucleus, β-catenin binds to transcription factors of the LEF/TCF family to promote target gene expression

Wnt

Wnt proteins are a large family of secreted glycoproteins that play an important role in cell and tissue growth and development (Xiao et al. 2023 ).Wnt proteins are lipidated in the endoplasmic reticulum by the O-acyltransferase Porcupine (PORCN) while being intracellularly transported and secreted via the membrane protein Wntless (WLS) (Qi et al. 2023 ). Overall, the mechanism of action of Wnt proteins is divided into two characteristic pathways: (a) the β-catenin-dependent pathway and (b) the β-catenin-independent pathway, which is subdivided into two types, including the planar cell polarity pathway (PCP) and the Wnt/Ca2 + pathway (Ashrafizadeh et al. 2020a , b ).Several types of Wnt proteins are known, including Wnt1-19, among which the Wnt1 gene was the first Wnt gene, introduced in 1982 while studying Drosophila melanogaster, and Wnt5a appears to be the major ligand of the non-classical pathway (Ashrafizadeh et al. 2020a , b ). However, compared with the β-catenin-independent pathway, the β-catenin-dependent pathway has been studied to a greater extent. These different types of Wnt proteins play different roles in biological growth, development, and energy metabolism. Therefore, further research on Wnt proteins can deepen the understanding of the occurrence and development of diseases, which can guide the treatment of related diseases.

Different types of Wnt proteins play different roles in disease development and treatment. For example, Wnt1 is closely associated with tumor diseases. Milosz Pietrus et al. reported that Wnt1 was associated with the grade and stage of endometrial cancers, with membranous Wnt-1 negatively associated with high-grade endometrial cancers, whereas cytoplasmic Wnt1 was positively correlated (Pietrus et al. 2023 ). In addition, for cervical cancer, Tie Xu et al. found that overexpression of NEK2 (a serine/threonine kinase involved in mitosis) promotes the development of cervical cancer and affects the sensitivity of cervical cancer to radiation therapy by activating the Wnt/β-catenin signaling pathway through Wnt1 (Xu et al. 2020 ). On the contrary, Guang-Lin Song et al. found that the microRNA miR-130a-3p (miR- 130a-3p) directly targets Wnt1, and miR-130a-3p can inhibit colorectal cancer(CRC) growth by reducing Wnt1 expression, suggesting a potential microRNA-based therapeutic strategy (Song et al. 2021 ). The Wnt2 is considered a proto-oncogene protein and is a tumor marker for gastric and CRC, and high expression of Wnt2 predicts a poor prognosis for colorectal and gastric (Liu et al. 2023a , b ; Lin et al. 2022 ). In addition, Wnt2 has also been associated with immunocompetence, and Tu-Xiong Huang et al. showed that Wnt2 secreted by cancer-associated fibroblasts (CAFs) inhibits dendritic cell-mediated antitumour T-cell responses through the SOCS3/p-JAK2/p-STAT3 signaling cascade (Huang et al. 2022 ).Wnt3 plays a role in embryonic development and neural tube formation. Stephan Niemann et al. found that Wnt3 is closely related to tetra-amelia, a human genetic disorder in which the complete absence of limbs is a major feature (Niemann et al. 2004 ). In addition, Wnt3 also plays an important role in radiation damage and radiation tolerance. Tong Yuan et al. found that Wnt3 not only promotes the recovery of intestinal stem cells caused by low-dose radiation, but also plays a key role in the inflammatory response and possible death of animals caused by high-dose radiation. This finding reveals that the Wnt3/β-catenin pathway may have dual roles under the influence of different doses of radiation, which can be an important factor in repairing the damage, but also a factor in exacerbating the damage when the radiation dose exceeds a certain threshold (Yuan et al. 2023 ). Jianbo Liu et al. found that chronic activation of the G protein-coupled estrogen receptor (GPER) promotes the proliferation of intestinal stem cells (ISCc) during menopause, a process that is mediated by the secretion of Wnt3 by paneth cells to activate the Wnt3/β-Catenin signaling pathway, which increases stem cell proliferation (Liu et al. 2023a , b ). In addition, HNF4α was found to be a regulator upstream of Wnt3 and paneth cells, a finding that has important implications for the understanding of intestinal health (Jones et al. 2023 ). In conclusion, Wnt proteins play different and multifaceted roles in different diseases, highlighting the complexity of these signaling molecules. Future studies can further delve into the mechanism of action of different Wnt proteins in disease development, as well as their potential application in clinical therapy, in the expectation that new therapeutic targets can be identified for related diseases and positively impact patient health.

The Wnt-β-catenin signaling pathway plays a crucial role in bone homeostasis by coordinating the differentiation and proliferation of osteoblasts and regulating osteoclast activity. We will focus on the effects of various factors including genetic modifications, environmental pollutants, oxidative stress, mechanical strain and pharmacological interventions on Wnt protein-mediated bone homeostasis. Shu Ma et al. demonstrated that in ankylosing spondylitis, microRNA-96 (miR-96) improves osteoblast differentiation and bone formation through activation of the Wnt signaling pathway, which was achieved by up-regulating the expression of Wnt1, β-catenin, and GSK-3β, as well as induced phosphorylation of β-catenin and GSK-3β activating the Wnt/β- catenin signaling pathway is achieved (Ma et al. 2019 ). Lu Wu et al. found that cadmium, as a common environmental pollutant, has a serious impact on bone health, especially cadmium chloride (CdCl2), which can reduce the protein levels of Wnt3a, β-catenin, LEF1, and TCF1 and thus inhibit osteogenic differentiation of bone marrow mesenchymal stem cells by suppressing the Wnt/β-catenin signaling pathway (Wu et al. 2019 ). In addition, the amount of Wnt ligand secreted in the body also affects bone formation. Lawsond et al. showed that mechanical stress promotes the gene expression of Wnt ligands, including Wnt1 and Wnt7b, which enhances the activity of the Wnt/β-catenin signaling pathway and promotes bone formation (Lawson et al. 2022 ).Notably, Wnt proteins not only promote osteoblast differentiation, but also affects osteoclasts. Osteoclasts also express typical Wnt receptors, and Megan M. Weivoda Ph.D et al. found that Wnt3a can activate β-catenin signaling and thus inhibit osteoclast differentiation, while Wnt3a can also inhibit osteoclast differentiation through activation of cAMP/PKA, which explains that the Wnt protein exhibits a dual regulatory roles in osteoblast and osteoclast differentiation (Weivoda et al. 2016 ). These findings further emphasize the importance of the Wnt/β-catenin signaling pathway in osteoblast differentiation. further highlight the important role of the Wnt signaling pathway in bone physiology and provide an important theoretical basis for the development of therapeutic strategies to target the Wnt/β-catenin signaling pathway.

β-catenin

Β-catenin was first discovered as a member of the Adhesion Junction, and was later found to be a core member of the Wnt/β-catenin signaling pathway. β-catenin is an armadillo family protein encoded by the CTNNbl gene, which is rich in the N-terminal Ser and Thr sites and regulates the stability of the molecule (Nichols et al. 2012 ). The C-terminus consists of 100 amino acids, which activates the transcription of target genes and promotes the initiation and extension of transcription by combining with a series of universal transcription cofactors, such as histone acetyltransferase and chromatin remodeling factor, etc. The intermediate linker arm is divided into 12 Arm repeats (R1 ~ R12), and forms a rod-shaped super-helical structure by the composition of 12 repeats and this structure can effectively prevent proteins from undergoing hydrolysis (Graham et al. 2000 ). The key to the Wnt/β-catenin signaling pathway lies in the presence of stable β-catenin in the cytoplasm, because β-catenin is an important signaling molecule for the transmission of Wnt signaling to the nucleus (Cheng et al. 2020 ).

As a key molecule in the Wnt/β-catenin signaling pathway, β-catenin has been widely demonstrated to have an important function in the development of various diseases. Dongying Wang et al. found that the expression of FAT4 was down-regulated in cervical cancer,but FAT4 could bind to β-catenin, prevent it from entering the nucleus, promote β-catenin phosphorylation and degradation, and effectively inhibit the pathological activation of Wnt/β-catenin signaling pathway. In addition, by limiting β-catenin activity, FAT4 is also able to reduce the expression of PD-L1 and STT3A and cause abnormal glycosylation and degradation of PD-L1, which may be beneficial for the enhancement of anti-tumor immune responses (Wang et al. 2023a , b ). Hui Hua et al. identified the oncogenic role of lncRNA LINC01226 in gastric cancer, and observed that LINC01226 was able to bind to STIP1 protein, which in turn promoted the dissociation of STIP1-HSP90 complex. This process enhanced the interaction between HSP90 and β-catenin and stabilized the expression level of β-catenin protein, thereby promoting its accumulation in the cell, and as a result, activated the Wnt/β-catenin signaling pathway, which ultimately contributed to the development of gastric cancer (Hua et al. 2023 ). Ruinan Tian et al. found that the scaffolding protein The receptor for activated C kinase 1 (RACK1) is closely related to tumor development. Proteasome 26S subunit non-ATPase 2 (PSMD2) is a novel binding chaperone of RACK1 and β-catenin. In breast cancer cells, RACK1 prevents ubiquitinated β-catenin from binding to PSMD2 to protect it from proteasomal degradation, thereby stabilizing β-catenin. This promotes the activation of Wnt/β- catenin signaling and the proliferation of cancer cells (Tian et al. 2023 ). Qing Wu et al. demonstrated that β-catenin plays an important role in the development and progression of diabetes mellitus (DM) and colon cancer. DM induces the shedding of platelet-endothelial cell adhesion molecule 1 (PECAM-1) from endothelial cells and its internalization and aggregation around the nucleus of the cells, which leads to the entry of β-catenin into the nucleus of the cells to promote the progression of colon cancer and endothelial-mesenchymal transition(EndMT) (Wu et al. 2023 ). Future studies can continue to explore the association between tumors and β-catenin. In addition, it is worthwhile to explore in depth the role of β-catenin in diabetic patients, especially in relation to EndMT. In addition to this, these studies have revealed potential therapeutic targets and strategies, such as using molecules such as NLRP12 and FAT4 to regulate the activation of the β-catenin signaling pathway, which may hold promise for the development of new therapeutic approaches. Future studies could further explore the therapeutic potential of these targets. Overall, these studies have opened up new research directions and therapeutic ideas, and future studies can further deepen the understanding of the role of β-catenin in different diseases and explore the prospects for its application in the clinic.

Recent studies have revealed that β-catenin plays an important role in skeletal physiology and pathology. Skeletal fluorosis, a bone metabolic disease, is characterized by accelerated bone turnover and abnormal osteoblast activity(Srivastava and Flora 2020 ). Yanru Chu et al. demonstrated that fluoride significantly increased cancellous bone formation and protein expression of Wnt3a, GSK3b, and Runx2 in mice; however, inhibition of β-catenin suppressed the fluoride-induced Runx2 protein expression and osteogenic phenotype, suggesting that β-catenin may be a therapeutic target for skeletal fluorosis (Chu et al. 2020 ). On the other hand, Sixu Chen et al. demonstrated that the therapeutic effect of PTH is attenuated in mice with type 1 diabetes, but when pre-activated with β-catenin in osteoblasts enhanced the anabolic effect of PTH on bone in mice with type 1 diabetes, significantly improving bone structure, bone volume and bone strength (Chen et al. 2020a , b ). In addition, Mark S Rybchyn et al. found that during skeletal mineralization in mice, the complex formed by the binding of calcium-sensing receptor (CaSR) and Homer1 was able to activate AKT via mTORC2 in response to extracellular calcium ion stimulation, thereby stabilizing β-catenin in osteoblasts, a process critical for promoting cell differentiation (Rybchyn et al. 2019 ). Whereas, Aditi Gupta et al. found that Connexin43 (Cx43), as an intercellular communication protein, can enhance Wnt-dependent and non-Wnt-dependent β-catenin signaling thereby modulating osteoblast function, bone regeneration, and bone metabolism by overlapping its function with β-catenin (Gupta et al. 2019 ). Microfibrillar-associated protein 5 (MFAP5) is a component of the extracellular matrix genes, which plays a crucial role in the regulation of cell motility and signaling, and Haoran Li et al. found that MFAP5 was able to promote osteoblast differentiation partly through the up-regulation of β-catenin and p-GSK-3β to activate the Wnt/β-catenin signaling pathway (Li et al. 2021 ). These studies deepen our understanding of the mechanisms of β-catenin's role in skeletal physiology and pathological processes.

Fzd

The Fzd receptor is a seven-transmembrane protein that is structurally similar to the G protein-coupled receptor. The extracellular N-terminus of the Fzd receptor is a ligand-binding region that binds to Wnt protein, is highly conserved, and is rich in cysteines (Dann et al. 2001 ). In addition, the intracellular C-terminus is capable of transmitting signals from the extracellular site to the Dvl, which inhibits the degradation of β-catenin and thus regulates the expression of the target gene (Tauriello et al. 2012 ; Huang and Klein 2004 ; Punchihewa et al. 2009 ).

Fzd proteins are associated with a wide range of biological functions and metabolism, thus causing the onset and progression of different diseases when Fed proteins are affected. Ding J et al. developed a specific alternative to Fzd4, L6-F4-2, which improves blood–brain barrier (BBB) or blood-retinal barrier (BRB) function by activating the Norrin/Fzd4/TSPAN12 pathway (Ding et al. 2023 ). This finding has implications for the treatment of neurodegenerative and ocular diseases involving barrier dysfunction. Zheng S et al. showed that Fzd5 differs from other Fzd proteins in that its conserved extracellular chain region binds cholesterol, which in pancreatic ductal adenocarcinoma (PDAC) promotes the growth of cancer cells through the activation of the Wnt/β-catenin signaling pathway by Fzd5 (Zheng et al. 2022 ). In addition, Lu P et al. found that deletion of the desert lncRNA HIDEN reduces the interaction between the IMP1 protein and the Fzd5 mRNA thereby leading to destabilization of the Fzd5 mRNA, which is necessary for endodermal differentiation (Lu et al. 2023 ). Wang L et al. demonstrated that in prostate cancer, GIPC2 can directly bind to Fzd7 through its PDZ structural domain, which activates the Wnt/β-catenin cascade to promote metastasis of prostate cancer cells (Wang et al. 2022a , b ). Notably, Fzd6 plays an important role as a key gene in the regulation of tissue polarity, and Dong B et al. demonstrated that knockdown or knockout of Fzd6 in melanoma reduced tumor cell invasion but did not affect proliferation (Dong et al. 2023 ). These studies have shown that Fzd proteins are involved in signaling pathways that affect a variety of physiological and pathological processes, including prostate cancer, PDAC, and human endodermal differentiation. Therefore, research on Fed proteins can help us to further understand the mechanisms of different diseases and develop new drugs targeting Fed proteins, which can provide new ideas for the treatment of diseases.

Fzd proteins serve as key members of the Wnt/β-catenin signaling pathway, which is critical for osteoblast function. Kushwaha P et al. found that matrix mineralization, expression of osteoblast differentiation markers, and response to Wnt3a were significantly attenuated in osteoblasts deficient in Fzd4, and furthermore, expression of Fzd8 was increased in Fzd4-deficient osteoblasts, which suggests that there may be some degree of functional overlap between Fzd4 and Fzd8 (Kushwaha et al. 2020 ). In addition, fibroblast growth factor (FGF) is thought to have an important role in osteoblast differentiation, and Ambrosetti D et al. found that genes of the Fzd Wnt receptor family (Fzd1, -2, -7, and -8 genes) that are downregulated by FGF, thereby inhibition osteoblast differentiation (Ambrosetti et al. 2008 ). In addition, Yu S et al. showed that the transcription factor Specificity protein 1 (Sp1) can regulate the expression of several genes, including those that are essential for growth and developmental processes, and that Sp1 can increase differentiation and mineralization of osteoblasts in vitro through the activation of Fzd1 (Yu et al. 2016 ). Wang J et al. demonstrated that miR-129-5p targets the Fzd4/β-catenin signaling pathway, inhibits osteoblast differentiation and reduces osteoblast markers (Wang et al. 2021 ). In conclusion, Fzd plays an important role in bone development and osteoblast differentiation and is influenced by a variety of factors. Therefore, research targeting Fzd may have great therapeutic potential for the treatment of skeletal diseases.

LRP5/6

LRP5/6 is a low-density lipoprotein receptor-related protein, a co-receptor characterized by a single transmembrane (Jeong and Jho 2021 ). In addition, it possesses an intracellular region and an extracellular region, each with different functions (Hofbauer et al. 2002 ). The intracellular region can interact with Axin and GSK-3 proteins due to the possession of PPPS/TPxS/T modules (Zeng et al. 2005 ; Wu et al. 2009 ). The extracellular domain can be further divided into the epidermal growth factor structural domain and the low-density lipoprotein receptor structural domain, where epidermal growth factor structural domain binds to Wnt and thus transmits signals(Balemans and Van Hul 2007 ).

LRP5/6 are key co-receptors in the Wnt/β-catenin signaling pathway that play critical roles in various physiological processes and have been implicated in the pathogenesis of different diseases. Borrell-Pagès M et al. found that the transcriptional regulation of LRP5 is influenced by aggregated low-density lipoprotein (agLDL) and that LRP5 is involved in macrophage lipid uptake and transformation to foam cells, which play a key role in influencing the onset and progression of atherosclerosis (Borrell-Pagès et al. 2011 ). Meanwhile, Lina Badimon et al. showed that both lipid uptake by macrophages involves two molecules, LRP5 and Protein Convertase Subtilisin/Kexin 9(PCSK9), and, interestingly, that LRP5 is also involved in the mechanism of PCSK9 release (Badimon et al. 2021 ). Wo D et al. showed that LRP5 deficiency exacerbates myocardial ischemic injury, demonstrating a protective effect of LRP5. Dkk1, an inhibitor of the Wnt/β-catenin pathway, enhances the injury response by inducing endocytosis and degradation of LRP5/6 (Wo et al. 2016 ). Xuemin He et al. demonstrated that the development of autosomal dominant polycystic kidney disease (ADPKD) is closely associated with the LRP5 variant, which has been observed to be involved in the development of tubular fibrosis through the direct regulation of the TGF-β/Smad signaling pathway (He et al. 2020 ). Selenoprotein P (SELENOP) is characterized by the presence of selenocysteine, which is mainly secreted by the liver.K Sandeep Prabhu showed that SELENOP is a Wnt signaling regulator, which interacts with Wnt3a and LRP5/6 to influence colorectal tumorigenesis (Prabhu 2023 ). Summarizing the above findings, it is clear that LRP5/6 play an important role in a variety of diseases. Future studies can further explore the regulatory mechanisms of LRP5/6 and find more targeted therapeutic strategies.

LRP5/6 is an important receptor widely involved in the regulation of skeletal cell function, which is critical for bone development, growth and maintenance of bone density. Ke Yu et al. identified circRNA422 in rat bone marrow mesenchymal stem cells (BMSC), which can promote BMSC proliferation and osteogenic differentiation by regulating the expression of SP7 and LRP5, and has a facilitating effect on the early osseointegration process (Yu et al. 2022 ). Shahida Moosa et al. found that osteogenesis imperfecta (OI) is one of the disorders associated with LRP, and that variants in LRP5 and LRP6 lead to the development of different types of deformities and disorders such as fracture fragility or oligodontia (Moosa et al. 2019 ). In contrast, Giulia Leanza et al. found that the Lrp5A214V mutation leads to high bone mass and improves bone microarchitecture and bone strength, as well as peripheral glucose metabolism, and could be an ideal treatment for the high risk of fracture in diabetes (Leanza et al. 2021 ). In addition, the study by Aimy Sebastian et al. demonstrated an enhanced role of Wnt3a in osteoblast proliferation and early differentiation, emphasizing the importance of LRP6 over LRP5 in mediating Wnt3a signaling (Sebastian et al. 2017 ). This is confirmed by the results of Yan C Riddle et al., who found that LRP5/6 play an important role in mature osteoblasts, and that the lack of either has an effect on bone density and bone structure, with the effect of LRP6 being more pronounced, suggesting that its role in osteoblasts is more critical than that of LRP5 (Riddle et al. 2013 ). Future studies can delve into the molecular mechanisms of LRP5 and LRP6 in skeletal cell biology and further reveal their association with bone diseases such as fracture healing and osteoporosis. Meanwhile, based on the in-depth understanding of LRP5/6, therapeutic strategies can be further explored, including the development of drugs and therapeutic approaches targeting their signaling pathways to better address clinical problems related to bone health.

Axin

Axin is a negative regulator of the Wnt/β-catenin signaling pathway and binds to several members of the Wnt/β-catenin signaling pathway. The N-terminal region is the binding region of APC and Axin, the middle region can bind GSK-3, β-catenin and CK1, and the C-terminal region is the region where Axin forms homo-oligomers, which is also known as the DIX structural domain.Axin contains both Axin1 and Axin2 family members and both are structurally similar (Hsu et al. 1999 ).Axin1 regulates the phosphorylation and stability of β-catenin by forming complexes with other proteins such as GSK-3β, APC, and CK1 (Koyama-Nasu et al. 2015 ). Axin2, although its expression pattern and function in cells differ from that of Axin1, plays an essential role in embryonic development, especially in in skeletal development (Hiremath et al. 2022 ). Recent studies have shown that Axin2 is associated with a variety of diseases and tumors related to the skeletal system.

In recent years, more and more diseases with abnormal expression or mutation of Axin have been identified, further demonstrating the important role of Axin in disease development. Xue-Lian Sun et al. study revealed a compelling cellular competition between neural progenitor cells (NPCs) during brain development that aims to weed out unsuitable cells and thus optimize organogenesis, a process triggered by genetic mosaicism of Axin2 and Trp53 (Sun et al. 2023 ). Lysophosphatidic acid (LPA) is an endogenous phospholipid that plays a crucial role in the regulation of cellular homeostasis and in the malignant behavior of cancer cells through G-protein-coupled receptors, Hosne Ara et al. found that LPA promotes gastric cancer development and progression, and one of the mechanisms includes LPA's ability to dysregulate energy metabolism through the LPAR2 receptor and Axin2 (Ara et al. 2022 ).Wenjia Li et al. found that RNF146, a RING-type E3 ubiquitin ligase, was modified by SUMOization, which further promoted its interbinding with Axin, accelerated Axin degradation and enhanced Wnt/β-catenin signaling, a process that contributes to the progression of hepatocellular carcinoma (Li et al. 2023 ). Sonu Singh et al. showed that knockdown of Axin2 promotes mitochondrial biogenesis and dopaminergic neurogenesis in a rat model of Parkinson's disease, which is achieved through modulation of the Wnt/β-catenin signaling pathway (Singh et al. 2018 ). Axin is abnormally expressed or mutated in a variety of diseases, further demonstrating its important role in disease occurrence and development. Further studies on the function and regulatory mechanism of Axin and exploration of its specific mode of action in different diseases will help to further reveal the regulatory network of the Wnt/β-catenin signaling pathway and provide a deeper understanding of the elucidation of the mechanism of disease occurrence.

Axin is an important protein that plays a significant role in a variety of cell differentiation and proliferation processes. In the skeletal system, the relationship between Axin and osteoblasts has also received increasing attention. MiR-16-5p is a miRNA that can regulate osteogenic differentiation. Jiaxin Duan et al. demonstrated that miR-16-5p in BMSC-derived extracellular vesicles (EVs) can achieve its function of promoting osteogenic differentiation by suppressing the expression of Axin2, providing a new mechanistic explanation of its important role in osteogenesis (Duan et al. 2023 ). In addition, Sarocha Suthon et al. showed that SNPrs9921222, an intronic variant of Axin1 associated with bone mineral density (BMD), can regulate the onset and progression of bone diseases in human osteoblasts by regulating Axin1 through GATA4 and estrogen receptor alpha (Erα) binding (Suthon et al. 2022 ). Further studies by Yoshinori Matsumoto et al. found that deficiency of the E3 ubiquitin ligase RNF146 leads to an increase in the stability of its substrate Axin1, which results in impaired Wnt3a-induced activation of β-catenin and reduced expression of Fgf18 in osteoblasts, which further interferes with the processes of osteoblast proliferation and differentiation (Matsumoto et al. 2017 ). Future studies can try to reveal the fine regulation mechanism of Axin in skeletal system development and diseases, look for the interactions between new miRNAs or gene polymorphisms and Axin, as well as the mechanism of cross-regulation of Axin with other signaling pathways, which may bring new breakthroughs in the diagnosis and treatment of skeletal system diseases.

APC

APC proteins with their large relative molecular mass can form functional complexes with Axin and GSK-3, among others, to regulate the protein level of β-catenin in the cytoplasm (Kimelman and Xu 2006 ). APC possesses both β-catenin and Axin binding domains (Suzuki et al. 2004 ).

APC is a very important cytoskeletal protein that plays a key role in many biological processes such as cell polarity, signal transduction and cell cycle regulation. APC is strongly associated with the development and occurrence of a variety of diseases includingCRC, gastric cancer, abnormal brain development and cognitive impairment. Jiazhuo He et al. found that H. pylori infection causes DNA damage in gastric stem and progenitor cells. However, DNA damage caused by H. pylori infection was also more severe when the APC gene was inactivated, a finding that suggests a role for APC in the association between H. pylori infection and gastric cancer development (He et al. 2023 ). Aruna S Jaiswal et al. found that N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) was able to induce colon cancer cells to enter into an arresting state similar to senescent cells, which was associated with reduced levels of APC proteins, in addition to loss of microtubule organization and reduction of telomeric DNA (Jaiswal et al. 2004 ). K B Kaplan et al. found that chromosome segregation in cells is closely linked to the APC gene, and that carrying a shortened APC gene results in defective chromosome segregation, and that during mitosis, APC localizes to the ends of micro- tubules embedded in kinetochores and forms a complex with the checkpoint proteins Bub1 and Bub3, while experiments have also demonstrated that APC is a high-affinity substrate for Bub kinase, further proving the important role of APC in mitosis (Kaplan et al. 2001 ).Yukako Yokota et al. demonstrated that APC have an important role in maintaining the polarity architecture of radial glia during brain development, and that in the absence of APC, radial glia lose their polarity and responsiveness to polarity-maintaining signals, resulting in altered cellular function as well as impaired cortical neuron generation and migration (Yokota et al. 2009 ). Also, J L Mohn et al. found that deletion of the APC gene in brain neurons leads to multiple comprehensive neurodevelopmental deficits, including learning and memory deficits and autism-like behaviors, and that deletion of APC in the hippocampus leads to increased density of synaptic spines, alterations in synaptic function, and associated changes in molecular modifications and cellular adhesion complexes (Mohn et al. 2014 ). Future studies could focus on delving deeper into the specific mechanisms of APC in disease development, especially in tumors and the nervous system, and looking for potential therapeutic strategies.

APC proteins play important regulatory roles in several biological processes, especially appearing to be crucial in regulating bone metabolism and osteoblast function. Razvan L Miclea et al. found that APC knockout in mouse MSC-like KS483 cells resulted in upregulation of the Wnt/β-catenin and BMP/Smad signaling pathways but osteogenic differentiation was completely inhibited, but the inhibitory effect of APC deletion on cellular differentiation could be mitigated by increasing the concentration of BMP-7 (Miclea et al. 2011 ). In addition, Jing Ge et al. found that genistein, a predominant soy isoflavon, can promote osteoblast differentiation through activation of the Wnt/β-catenin signaling pathway by the mechanism that genistein by facilitating the activation of autophagy via the transcription factor EB (TFEB), which allows for the degradation of APC,emphasizing the potential therapeutic potential of pharmacological means to treat bone diseases (Ge et al. 2023 ).

GSK-3

GSK-3 is a serine/threonine kinase, between the two structural domains of the C-terminal end of the α-helix and the N-terminal end of the β-fold is the binding pocket ATP ( a homologue of AMP-NP), and this catalytic region mainly consists of amino acid residues such as Lys85, Thr138, Asp133 and Gin185 (Capurro et al. 2020 ).In the Wnt/β-catenin signaling pathway, the mechanism by which GSK-3 plays a negative regulatory role involves phosphorylating β-catenin to promote its degradation; whereas in the positive regulation of this signaling pathway, GSK-3 acts by phosphorylating LRP6 to promote the expression of positive regulators (Takahashi-Yanaga 2013 ).

Diseases associated with GSK-3 are an area of great interest. GSK-3 plays an important role in cell signaling and is involved in the regulation of a variety of biological processes, including cell proliferation, apoptosis, neurodevelopment and metabolic regulation. Jibin Zhou et al. found that GSK-3 in cardiomyocytes plays an important role in cardiac homeostasis and overall survival, and that the absence of GSK-3 in cardiomyocytes leads to disturbances in mitotic categorization, which ultimately leads to dilated cardiomyopathy (Zhou et al. 2016a , b ). Alonso Sánchez-Cruz et al. demonstrated that the loss of photoreceptor cells caused by retinitis pigmentosa (RP), a group of inherited neurodegenerative diseases of the retina, could be reduced when the GSK-3 inhibitor VP3.15 was used and that visual function was protected, and that this protection was achieved by reducing the expression of neuroinflammatory markers (Sánchez-Cruz et al. 2018 ). Andrey Ugolkov et al. demonstrated that two novel small-molecule GSK-3 inhibitors (9-ING-41 and 9-ING-87) were effective in decreasing the viability of breast cancer cells, and that 9-ING-41 also enhanced the efficacy of the chemotherapeutic drug irinotecan (CPT-11) (Ugolkov et al. 2016 ). Silvia guill-luna et al. highlighted that Tumor budding grade III CRC is associated with elevated GSK-3 expression levels as well as increased PD-L1 expression in tumor cells. Notably, inhibition of GSK-3 reduced tumor budding through necrotic and apoptotic pathways as well as significantly increased activated immune cells to enhance anti-tumor responses compared to PD-L1/PD-1 blockade approaches, suggesting that GSK-3 is involved in the regulation of tumor differentiation in CRC and may be involved in immune evasion mechanisms (Guil-Luna et al. 2023 ).

GSK-3, as a signal-regulating molecule, plays an important regulatory role in osteoblasts and osteoclasts. An in-depth study of its role in osteoblasts and osteoclasts is conducive to a better understanding of the mechanisms of metabolic regulation of bone, and provides new ideas and approaches for the treatment of related diseases. Alessandra Gambardella et al. found that the use of the GSK-3 inhibitor AR28 when used allowed endogenous mesenchymal progenitor cells with osteogenic and adipogenic potential to differentiate towards osteogenesis, but that this promotion of differentiation came at the expense of a certain amount of adipogenicity (Gambardella et al. 2011 ). Masaki Arioka et al. found that osteoclast differentiation was inhibited while osteoblast differentiation was enhanced when Li2CO3 was used locally as a GSK-3 inhibitor, revealing the potential application of lithium as a GSK-3 inhibitor in the treatment of bone injuries (Arioka et al. 2014 ). These findings provide new ideas and avenues for understanding the mechanisms of metabolic regulation of bone and the treatment of related diseases.

CK1

CK1 was one of the first protein kinases found to have serine/threonine protein activity and is involved in the regulation of cellular signaling as well as gene expression (Knippschild et al. 2005 ).It is widely distributed in eukaryotes, and seven isoforms have been identified in mammals, including α, β, γ1, γ2, γ3, δ, and ε (Cheong and Virshup 2011 ). The N-terminal end of CK1 is a highly conserved structural domain of the kinase, which consists of 290 amino acid residues, with a large variation in the C-terminal end, which varies in length from 40 to 180 amino acids (Knippschild et al. 2005 ).

With the increasing research on CK1, a number of diseases associated with CK1 have been identified, and the role of CK1 in the development of these diseases has been gradually revealed. Maureen Spit et al. showed that the environmentally independent self-renewal of cancer cells is driven by truncating mutations in RNF43, which prevent the degradation of β-catenin by immobilizing CK1 at the cell membrane, leading to the sustained activation of transcription of target genes, suggesting that truncating mutations in RNF43 play an important role in the development of cancer (Spit et al. 2020 ). Marilena Carrino et al. found that the survival of multiple myeloma (MM) cells is also closely related to CK1, and that by inhibiting CK1 activity or lowering the level of CK1, autophagic activity and promoting apoptosis in multiple myeloma cells can be reduced, thereby inhibiting tumor growth and survival (Carrino et al. 2019 ).Yumeng Zhang et al. demonstrated that nicotinamide promoted the differentiation of pancreatic progenitor cells by inhibiting CK1 and ROCK, and demonstrated that inhibition of CK1α and CK1ε promoted the differentiation of pancreatic progenitor cells (Zhang et al. 2021 ).

Regarding the relationship between CK1 and osteoporosis, no directly relevant research results have been found in the literature. However, according to the currently known information, CK1 plays an important role in the Wnt/β-catenin signaling pathway, which is closely related to the processes of cell proliferation and differentiation, etc. Although it is not clear that there is a relationship between CK1 and the pathogenesis of osteoporosis, from the aspect of its biological roles, we can hypothesize that there exists a little bit of a link between CK1 and osteoporosis, so that in the future research can further explore the potential role of CK1 in the pathogenesis of osteoporosis.

Dvl

Dvl is a periplasmic protein that is ubiquitous in organismal tissue cells and is essential for intracellular transmission of the Wnt/β- catenin signaling pathway. The Dvl protein contains three major structural domains; the N-terminus contains the DIX region consisting of 51 amino acids, the middle portion is the PDZ region, which is a basic sequence consisting of 80–90 amino acids present within more than 50 proteins such as PSD-95 and ZO-1, and the C-terminus contains the DEP region, which is capable of binding to the Dvl, EGL10, and Pleckstrin proteins (Gan et al. 2008 ).

Dvl protein, as an important signal-regulating protein, plays an important role in the processes of cell development, tissue repair, and disease development, and its aberrant function and regulatory imbalance are closely related to the occurrence of many diseases. Vincent C Pai et al. found that the expression of ASPM (a novel Wnt coactivator) was progressively up-regulated in primary and metastatic prostate cancer and that ASPM interacted with Dvl-3 to inhibit the enzymesome-dependent degradation and to increase the protein stability of Dvl-3, which enhances Wnt-induced β-catenin transcriptional activity thereby contributing to the development of prostate cancer (Pai et al. 2019 ). Lingling Liu et al. found that mutations in the Dvl gene were present in human patients with neural tube defects and Dandy-Walker malformations, which resulted in blockage of the Wnt/β-catenin signaling pathway, in addition to the finding that only the Dvl2 p.R633W mutation showed more severe malformations in zebrafish embryos when compared to wild-type Dvl2 toxicity, revealing the important role of Dvl mutations in the pathogenesis of human neurological diseases (Liu et al. 2020 ).

In the skeletal system, Dvl has also been found to play an important role in osteoblast function. The following section will focus on the regulatory role of Dvl in osteoblasts and its importance to the health of the skeletal system. H-Y Kim et al. found that CXXC finger protein 5 (CXXC5) is a negative feedback regulator of the Wnt/β-catenin pathway, which can inhibit osteoblast differentiation and bone formation, and the main mechanism of this is that CXXC5 exerts a negative feedback effect by binding to Dvl (Kim et al. 2015 ).Fangfang Zhou et al. identified a protein called ubiquitin-specific enzyme 4 (USP4), which inhibits osteoblast differentiation by removing the Lysine-63-linked polyubiquitin chain on Dvl forming an inhibitory effect on Wnt/β-catenin signaling (Zhou et al. 2016a , b ) (Table 1 ). Table 1 Wnt/β-catenin signalling targets and their effects on osteoblasts and osteoclasts Research target Alterations in Wnt/β-catenin signaling Effects on osteogenesis References miR-96 Wnt1, β-catenin and GSK-3β Promotes osteoblast differentiation and bone formation Ma et al. ( 2019 ) CdCl2 Wnt3a,β-catenin,LEF1 and TCF1 Inhibition of osteoblast differentiation Wu et al. ( 2019 ) Mechanical pressure Wnt1 and Wnt7b Promotes bone formation Lawson et al. ( 2022 ) Wnt3a β-catenin Causes inactivation of NFATc1 and inhibits osteoclast differentiation Weivoda et al. ( 2016 ) Fluoride Wnt3a, GSK3b and Runx2 Increasescancellous bone formation in mice Chu et al. ( 2020 ) CaSR and Homer1 complexes β-catenin Promote osteoblast differentiation Rybchyn et al. ( 2019 ) Cx43 β-catenin Regulation of osteoblast function, bone regeneration and bone metabolism Gupta et al. ( 2019 ) MFAP5 β-catenin and GSK3b Promotes osteoblast differentiation Li et al. ( 2021 ) FGF Fzd1, -2, -7, and -8 Inhibition osteoblast differentiation Ambrosetti et al. ( 2008 ) Sp1 Fzd1 Increase differentiation and mineralization of osteoblasts in vitro Yu et al. ( 2016 ) miR-129-5p Fzd4 and β-catenin Inhibits osteoblast differentiation Wang et al. ( 2021 ) circRNA422 LRP5 Promotes osteoblast differentiation and facilitates osseointegration Yu et al. ( 2022 ) Lrp5A214V LRP5 Improves bone microarchitecture and bone strength Leanza et al. ( 2021 ) MiR-16-5p Axin2 Promotes osteogenic differentiation Duan et al. ( 2023 ) SNP rs9921222 Axin1 Regulate the onset and progression of bone diseases in human osteoblasts Suthon et al. ( 2022 ) RNF146 Wnt3a, β-catenin and Axin1 Inhibition of osteoblast proliferation and differentiation Matsumoto et al. ( 2017 ) Genistein APC Promote osteoblast differentiation Ge et al. ( 2023 ) AR28 GSK-3 Promoting differentiation of endogenous mesenchymal progenitor cells towards osteogenesis Gambardella et al. ( 2011 ) Li2CO3 GSK-3 Osteoclast differentiation is inhibited while osteoblast differentiation is enhanced Arioka et al. ( 2014 ) CXXC5 Dvl Inhibits osteoblast differentiation and bone formation Kim et al. ( 2015 ) USP4 Dvl Inhibits osteoblast differentiation Zhou et al. ( 2016a , b )

Natural compound

The Wnt/β-catenin signaling pathway is one of the key mechanisms regulating bone metabolism, which influences osteogenic activity and osteoclastogenesis, and maintains the health and regeneration of bone tissue (Lin et al. 2024 ). However, for how to precisely modulate the Wnt/β-catenin signaling pathway for the treatment of diseases including osteoporosis, fracture and other diseases related to bone loss is still a major challenge for current research. For compounds from nature, which are increasingly valued due to their potential bioactivity and therapeutic potentials, we will summarize important natural compounds that have been found to interact with the Wnt/β-catenin signaling pathway, which will provide new strategies for the treatment of diseases (Fig. 2 ). Fig. 2 Schematic diagram of Wnt signalling regulation of osteoblasts and osteoclasts. In osteoblasts, β-catenin-dependent classical signalling induces bone formation by promoting osteoblastogenesis and upregulating OPG expression. Non-β-catenin-dependent atypical signalling enhances LRP5/6 expression and promotes osteoblast differentiation. runx1 activates Wnt signalling by increasing Wnts expression and promotes osteoblast differentiation. Non-canonical Wnt5a signalling via ROR2 activates RhoA, which is necessary and sufficient for osteoblast differentiation. In addition, Wnts also promote osteoblast differentiation and bone formation through PLC/PKCδ signalling. In osteoblasts, classical Wnt signalling inhibits bone resorption, while non-classical Wnt signalling promotes bone resorption.Wnt5a-ROR2 signalling enhances RANKL-induced osteoclastogenesis by increasing RANK expression through activation of c-Jun.The Wnt5a-ROR2 signalling pathway activates Rho in an adaptor-dependent manner with the aptamer protein Daam2.Subsequently, the Rho effector kinase Pkn2 activates Rho. Subsequently, the Rho effector kinase Pkn3 binds to c-Src and promotes actin ring formation, thereby increasing bone resorption. Wnt4 and Wnt16 inhibit RANKL-induced activation of NF-kB and NFATc1 signalling, thereby inhibiting osteoclast differentiation

A variety of different tissues and organs such as the myocardium, liver, thyroid, adrenal glands, white adipose tissue, and central nervous system release a substance called irisin, which is a muscle-derived factor and is released during exercise (Dun et al. 2013 ; Aydin et al. 2014 ). The differentiation of osteoblasts decreases under microgravity, but Zhihao Chen et al. showed that irisin promotes the expression of the osteogenic marker genes Alp, ColIα1, and also promotes osteoblasts differentiation under microgravity by increasing the expression of β-catenin (Chen et al. 2020a , b ).

Curculigo orchioides, a traditional Chinese medicine, can treat a variety of diseases including bone atrophy, osteoporosis, and numbness of the limbs (He et al. 2019 ). The main bioactive components of curculigo orchioides include polysaccharides, phenolics, novolacins and terpenoids (Wang et al. 2021 ). COP70-1 is a bioactive ingredient isolated from curculigo orchioides that promotes osteoblast differentiation.One of the mechanisms is that COP70-1 induces GSK-3β phosphorylation in a concentration-dependent manner thereby increasing the stabilization and accumulation of β-catenin proteins and transferring them to the nucleus, initiating the expression of TCF/LEF-1, which promotes osteogenesis by mediating the Wnt/β-catenin signaling pathway (Wang et al. 2023a , b ).

Ginkgolide B (GB) is a bioactive ingredient isolated and purified from Ginkgo biloba. It is widely used for its antitumor and anti-inflammatory activities, Bing Yao et al. has found that GB has an inhibitory effect on prostate cancer (Yao et al. 2017 ).Bin Zhu et al. have demonstrated that GB promotes ALP activity and mineralization in osteoblasts, and upregulates genes that are hallmarks of osteoblast differentiation, such as Col I, Runx2, Osterix, OCN, and OPN, and that the mechanism of this is that GB promotes differentiation of osteoblasts by increasing the level of Ser9 phosphorylation of GSK-3β, upregulating the expression of β-catenin, and activating Wnt/β-catenin signaling (Zhu et al. 2019 ).

Paeonia lactiflora (PL) is often used to treat a variety of conditions such as irregular menstruation and dysmenorrhea, and has a variety of biological activities such as anti-inflammatory, anti-cancer, and anti-pigmentation. Albiflorin, the main active ingredient in peony, is essentially a monoterpene glycoside. Albiflorin is able to prevent osteoporosis through antioxidant action (Suh et al. 2013 ) and also reduces inflammation in the lungs (Cai et al. 2019 ) and improves memory deficits (Xu et al. 2019 ). Recently, Jae-Hyun Kim et al. found that albiflorin can promote osteoblast differentiation and mineralization. Albiflorin increased the protein expression of BMP-2, RUNX2, and OSTERIX as well as the phosphorylation of Smad, which suggests that it can stimulate bone production through the BMP-2/Smad signaling pathway. In addition, it was found to increase the mRNA expression of Wnt10b, β-catenin, LRP5, LRP6, Dvl2, and cyclin D1, which demonstrated that it could stimulate osteoblast differentiation and regeneration through the Wnt/β-catenin signaling pathway (Kim et al. 2021 ).

3,5-dicaffeoyl‐epi-quinic acid(DCEQA), a substance extracted from atriplex gmelinii, is a derivative of chlorogenic acid and is biologically active. Anti-obesity and UV photoprotective effects of DCEQA have been reported. Recently, Fatih Karadeniz et al. demonstrated that treatment of human bone marrow mesenchymal stromal cells (hBM-MSCs) with DCEQA promotes their differentiation to osteoblasts, as well as enhances ALP activity and cellular mineralization, and one of the main mechanisms of this is that DCEQA increases the levels of Wnt 10a and Axin proteins, as well as phosphorylation of β-catenin, which promotes the Wnt/β-catenin signaling pathway and thus enhances osteoblasts' differentiation (Karadeniz et al. 2020 ).

Euodia sutchuenensis Dode (ESD) is an ornamental tree species which grows in temperate regions. ESD has a high medicinal value, relieving headaches, gastritis and dermatitis, in addition to the anti-mold activity of the geranylfuranocoumarins in its fruits (Stevenson et al. 2003 ; Adams et al. 2006 ). Recently, Jeong-Ha Hwang et al. found that ESD extract may have therapeutic potential for the treatment of osteoporosis. They found that ESD extract was able to enhance the ALP activity and mineralization capacity of osteoblasts, and that the expression of osteoblast differentiation marker genes, such as BMP2, RUNX2, and COL1A1, was increased after treatment with ESD extract, and that the mechanism was that ESD extract increased β-catenin levels in osteoblasts, thereby activating the Wnt/β-catenin signaling pathway (Hwang et al. 2015 ).

Geraniin is a substance with a wide range of biological activities extracted from phyllanthus amarus, which is essentially a cyclic tannin. Geraniin has a wide range of anti-inflammatory, antioxidant, anti-infectious, anti-tumor, anti-hyperglycemic and anti-hypertensive properties (Boakye et al. 2016 ; Aayadi et al. 2017 ; Liu et al. 2016 ; Ren et al. 2017 ; Elendran et al. 2015 ; Patel et al. 2011 ). Kejia Li et al. demonstrated that Geraniin also has a promotional effect on the differentiation and proliferation of osteoblasts. Geraniin treatment enhanced the expression of a series of proteins related to the Wnt/β-catenin pathway (including β-catenin, Fzd2, LRP6, etc.), while inhibiting the expression of Axin2 (Li et al. 2018 ). These results suggest that Geraniin may enhance osteoblast function by activating the Wnt/β-catenin pathway.

Astragalus is a Chinese herb with a variety of biological activities including anticancer, anti-inflammatory, and antioxidant. Of interest is that astragalus inhibits bone loss in ovariectomized mice (Xia et al. 2014 ). Astragaloside I (As-I) is the main active ingredient of Astragalus membranaceus. Xun Cheng et al. found that As-I stimulated osteoblast differentiation, increased ALP activity and its mineralization capacity, and the main mechanism was that As-I increased the expression of β-catenin and Runx2 proteins thereby enhancing the Wnt/β-catenin signaling pathway (Cheng et al. 2016 ).

Bergamottin (BM), a natural compound, is mainly extracted from a variety of citrus fruits. It has a variety of biological activities, including anti-adipogenesis, antioxidant and anti-cancer, etc. (Jung et al. 2021 ; Ko et al. 2018 ). Recently, Xue Wang et al. found that BM was able to regulate the Wnt/β-catenin signaling pathway by increasing the expression of LRP6, Wnt3a and β-catenin as well as decreasing the expression of GSK-3β to promote osteoblasts differentiation attenuating the loss of bone mass and improving bone turnover in OVX-induced osteoporosis in mice (Wang et al. 2022a , b ).

Psidium guajava has been found to have significant efficacy in slowing down a number of metabolic diseases such as diabetes, obesity and osteoporosis (Devalaraja et al. 2011 ).Konica Porwal et al. isolated gallic acid, ursolic acid (UA), 2α-hydroxyursolic acid (2α-UA), β-sitosterol and β-sitosterol-D-glucoside from guava extract (GE). Among them, only UA and 2α-UA enhanced ALP activity and mineralization capacity of osteoblasts, and the main mechanism was that 2α-UA was able to up-regulate the mRNA levels of Runx2 and Wnt3a, whereas UA was able to increase the levels of BMP-2, Col1 and Wnt3a in osteoblasts, thereby enhancing the Wnt/β-catenin signaling pathway (Porwal et al. 2017 ).

Gigas are a nutrient-rich food. Fermented Oyster Extract (FO) is rich in protein and carbohydrates. In addition, lysine and GABA are the most abundant amino acids in FO. These nutrients may have an important role in human health and bone production. Ilandarage Menu Neelaka Molagoda et al. found that FO promoted osteoblast differentiation and increased the expression of specific marker proteins such as RUNX2, ALP, Col1α1, OCN, OSX, and BMP4, as well as increased osteoblast ALP activity and mineralization capacity. One of the mechanisms is the ability of FO to significantly increase the expression of β-catenin, which activates the Wnt/β-catenin signaling pathway (Molagoda et al. 2019 ).This is important for promoting osteogenesis and maintaining bone health.

Polygonatum sibiricum polysaccharide (PSP) is a substance extracted from the traditional Chinese medicine Polygonum sibiricum. It has a variety of biological activities, including anti-inflammatory and attenuating amyloid-β-induced neurotoxicity (Zhang et al. 2015 ). Li Du et al. found that PSP were able to promote the differentiation of bone marrow mesenchymal stem cells to osteoblasts, and enhanced the ALP activity and mineralization capacity of osteoblasts. In addition, PSP increased the expression of osteogenic differentiation genes, including COL I, ALP, Runx2 and OCN. The main mechanism is that PSP increase the expression and activation of β-catenin, promoting the accumulation of β-catenin in the nucleus and subsequently interacting with the transcription factor TCF/LEF to activate the Wnt/β-catenin signaling pathway, thereby promoting osteoblastogenesis and function (Du et al. 2016 ).

Soybean isoflavones (SI) are a class of natural compounds found in soybeans and belong to the isoflavones group. SI mainly include soy glycosides, soy glycosides and soy brassinas, which are considered phytoestrogens and can mimic the effects of estrogen (Cederroth et al. 2010 ). Studies have shown that SI have a variety of biological activities including antioxidant, anti-inflammatory, anti-tumor, lipid-lowering and bone density improvement. Fang Yu et al. demonstrated that SI can promote osteoblast differentiation and enhance osteoblast ALP activity and its mineralization capacity, the main mechanism of which is that an increase in the concentration of soy isoflavones can increase the expression level of Wnt3a, Wnt7b, and β-catenin proteins and activate the Wnt3a/β-catenin signaling pathway (Yu et al. 2015 ).

Arbutin, a natural compound extracted from a variety of plants including bearberry leaves, pears, and marjoram (Lamien-Meda et al. 2009 ), is a natural hydroquinone derivative. Arbutin has a variety of biological activities, including whitening, anti-inflammatory and protection against oxidative stress (Lim et al. 2009 ; Wu et al. 2014 ). Xiangji Man et al. found that arbutin promotes osteoblast differentiation and increases ALP activity and its mineralization capacity, the main mechanism of which is that arbutin significantly increases the protein expression levels of Runx2 and β-catenin, thus promoting osteoblast differentiation through the typical Wnt/β-catenin pathway (Man et al. 2019 ).

Kirenol is a natural compound isolated from Herba Siegesbeckia, including S. orientalis, S. glabrescens, and S. pubescens, and is a diterpene compound (Xiang et al. 2004 ). Kirenol has biological activities with antioxidant, anti-inflammatory, anti-allergic, anti-adipogenic and anti-arthritic properties (Xiang et al. 2004 ; Jiang et al. 2011 ; Huo et al. 2013 ). Mi-Bo Kim et al. demonstrated that Kirenol can promote osteoblast differentiation and increase the ALP activity and mineralization capacity of osteoblasts, and one of the main mechanisms is that Kirenol increases the mRNA expression of LRP5, Dvl2, β-catenin, and CCND1 genes, and then up-regulates the activity of Wnt/β-catenin signaling pathway (Kim et al. 2014 ).

Cajanus cajan (L.) Millsp. is a traditional Chinese herb whose fresh leaves are used to treat a variety of ailments including parasitic diseases, oxidative damage, and cancer (Duker-Eshun et al. 2004 ). Shan Liu et al. found that Cajanolactone A (CLA), a stilbene extracted from Cajanus cajan (L.) Millsp, has a promotional effect on osteoblast differentiation, and that the main mechanism is that it can significantly upregulate the mRNA levels of Wnt3a, Wnt10b, LRP5, Frizzled 4, β-catenin, Runx2, and Osterix, suggesting that CLA promotes osteoblast differentiation by stimulating Wnt/β-catenin signaling pathway (Liu et al. 2019 ) (Table 2 ). Table 2 Effects of natural compounds on the Wnt/β-catenin signaling pathway Compound Source Molecular structure Dosages Effects of the Wnt/β-catenin signaling pathway References Irisin Muscle 0、1、5、10 nM β-catenin Chen et al. ( 2020 ) GB Ginkgo 0、5、10、20 µmol/L GSK- 3β、β-catenin Zhu et al. ( 2019 ) Albiflorin PL 0、20、40、60 µg/ml Wnt10b、β-catenin、LRP5、LRP6、Dvl2 Kim et al. ( 2021 ) DCEQA Atriplex gmelinii 0、1、5、10 µM Wnt 10a、Axin、β-catenin Karadeniz et al. ( 2020 ) Geraniin Phyllanthus amarus 0、0.01、0.1、1、10 nM β-catenin、Fzd2、LRP6、axin2 Li et al. ( 2018 ) As-I Astragalus 0、10、20、40 µM β-catenin、Runx2 Cheng et al. ( 2016 ) BM Citrus fruits 0、5、10、20 µM LRP6、Wnt3a、β-catenin、GSK-3β Wang et al. ( 2022a , b ) UA GE 100 pM Wnt3a、BMP-2、Col1 Porwal et al. ( 2017 ) 2α-UA GE 100 pM Wnt3a、Runx2 Porwal et al. ( 2017 ) Arbutin Bearberry leaves, pears, marjoram 0、10、50、100 µM Runx2、β-catenin Man et al. ( 2019 ) Kirenol Herba Siegesbeckia 0、10、20、40 µM LRP5、Dvl2、β-catenin、CCND1 Kim et al. ( 2014 ) CLA Cajanus cajan (L.) Millsp. 0、1、2、4 µM Wnt3a、Wnt10b、LRP5、Fzd4、β-catenin、Runx2、Osterix Liu et al. ( 2019 ) COP70-1 Curculigo orchioides – 0、0.8、1.6、3.2 µM GSK- 3β、β-catenin Wang et al. ( 2023a , b ) ESD Extract ESD – 0、1、5 µg/ml β-catenin Hwang et al. ( 2015 ) FO Gigas – 0、50、100 µg/ml β-catenin Molagoda et al. ( 2019 ) PSP Polygonum sibiricum – 0、5、10、25、50、100 mg/l β-catenin Du et al. ( 2016 ) SI Soybean – 0、0.1、0.2、0.3 M Wnt3a、Wnt7b、β-catenin Yu et al. ( 2015 )

Conclusions

With the increasing understanding of the Wnt/β-catenin signaling pathway, it has been found that alterations in different proteins in the pathway can cause disease consequences such as cancer, osteoporosis, and dysplasia. The Wnt/β-catenin signaling pathway is known to play a key role in osteoblast differentiation and bone formation. By regulating this pathway, bone formation can be promoted, bone mineral density can be increased, and fracture risk can be reduced. Targeted therapeutic regimens against the Wnt/β-catenin signaling pathway have proven to be promising options for treating diseases. Clinically, therapeutic strategies targeting this pathway, especially small molecule drugs and natural compounds, have shown promising therapeutic effects, which can provide new treatment options for patients with osteoporosis, improve the quality of life of patients, and reduce the disability and complications caused by osteoporosis. It is expected that further studies will be conducted in the future, and effective treatments centered on the Wnt/β-catenin signaling pathway have been identified.

In cancer treatment, the abnormal activation of Wnt/β-catenin signaling pathway is closely related to the occurrence and development of a variety of cancers. Clarifying the specific mechanism of this pathway in different cancers will help to develop specific targeted therapeutic drugs. By inhibiting the over-activation of this pathway, the proliferation, invasion and metastasis of cancer cells can be prevented and the effect of cancer treatment can be improved. In addition, gene modification and other technologies also provide new ideas and methods for the precision treatment of cancer.

In conclusion, the in-depth study of Wnt/β-catenin signaling pathway provides new direction and hope for the treatment of diseases such as osteoporosis and cancer, which has important clinical application value. Future research should further explore the regulatory mechanism of this pathway, develop safer and more effective treatment methods, and provide strong support for clinical treatment.

Abbreviations

Colorectal cancer

G protein-coupled estrogen receptor

Intestinal stem cells

MicroRNA-96

Cadmium chloride

Receptor for activated C kinase 1

Diabetes mellitus

Platelet-endothelial cell adhesion molecule 1

Endothelial-mesenchymal transition

Calcium-sensing receptor

Connexin43

Blood–brain barrier

Blood-retinal barrier

Pancreatic ductal adenocarcinoma

Fibroblast growth factor

Specificity protein 1

Aggregated low-density lipoprotein

Protein Convertase Subtilisin/Kexin 9

Autosomal dominant polycystic kidney disease

Selenoprotein P

Bone marrow mesenchymal stem cells

Osteogenesis imperfecta

Neural progenitor cells

Lysophosphatidic acid

Extracellular vesicles

Bone mineral density

N-Methyl-N'-nitro-N-nitrosoguanidine

Retinitis pigmentosa

Multiple myeloma

CXXC finger protein 5

Ubiquitin-specific enzyme 4

Ginkgolide B

Paeonia lactiflora

3,5-Dicaffeoyl‐epi-quinic acid

Euodia sutchuenensis Dode

Astragaloside I

Bergamottin

Ursolic acid

2α-Hydroxyursolic acid

Guava extract

Fermented oyster extract

Polygonatum sibiricum polysaccharide

Soybean isoflavones

Cajanolactone A

Microfibrillar-associated protein 5

Proteasome 26S subunit non-ATPase 2

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Xiaohao Wang and Zechao Qu have contributed equally to this work.

Acknowledgements

Not applicable.

Author contributions

XHW and ZCQ conceived the idea and wrote the manuscript. SCZ and LL collected the literature together. LY modified the manuscript critically for important intellectual content and final approval of the version to be published. All authors reviewed and approved the final manuscript.

Funding

This study was funded by the National Natural Science Foundation of China (82260181), Key project of Natural Science Basic Research Plan of Shaanxi Province (2022JZ-43), Medical Research Project of Xi’an Science and Technology Bureau (24YXYJ0102), and Medical Research Project of Xi’an Science and Technology Bureau (24YXYJ0006).

Availability of data and materials

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

Aayadi H Mittal SPK Deshpande A Gore M Ghaskadbi SS Protective effect of geraniin against carbon tetrachloride induced acute hepatotoxicity in Swiss albino mice Biochem Biophys Res Commun 2017 487 1 62 67 10.1016/j.bbrc.2017.04.013 28396147 Aayadi H, Mittal SPK, Deshpande A, Gore M, Ghaskadbi SS. Protective effect of geraniin against carbon tetrachloride induced acute hepatotoxicity in Swiss albino mice. Biochem Biophys Res Commun. 2017;487(1):62–7. 28396147 10.1016/j.bbrc.2017.04.013

Adams M Ettl S Kunert O Wube AA Haslinger E Bucar F Antimycobacterial activity of geranylated furocoumarins from Tetradium daniellii Planta Med 2006 72 12 1132 1135 10.1055/s-2006-947239 16981128 Adams M, Ettl S, Kunert O, Wube AA, Haslinger E, Bucar F, et al. Antimycobacterial activity of geranylated furocoumarins from Tetradium daniellii. Planta Med. 2006;72(12):1132–5. 16981128 10.1055/s-2006-947239

Ambrosetti D Holmes G Mansukhani A Basilico C Fibroblast growth factor signaling uses multiple mechanisms to inhibit Wnt-induced transcription in osteoblasts Mol Cell Biol 2008 28 15 4759 4771 10.1128/MCB.01849-07 18505824 PMC2493354 Ambrosetti D, Holmes G, Mansukhani A, Basilico C. Fibroblast growth factor signaling uses multiple mechanisms to inhibit Wnt-induced transcription in osteoblasts. Mol Cell Biol. 2008;28(15):4759–71. 18505824 10.1128/MCB.01849-07 PMC2493354

Ara H Subedi U Sharma P Bhattarai S Sharma S Manikandan S Alteration of cellular energy metabolism through LPAR2-Axin2 axis in gastric cancer Biomolecules 2022 12 12 1805 10.3390/biom12121805 36551233 PMC9775664 Ara H, Subedi U, Sharma P, Bhattarai S, Sharma S, Manikandan S, et al. Alteration of cellular energy metabolism through LPAR2-Axin2 axis in gastric cancer. Biomolecules. 2022;12(12):1805. 36551233 10.3390/biom12121805 PMC9775664

Arioka M Takahashi-Yanaga F Sasaki M Yoshihara T Morimoto S Hirata M Acceleration of bone regeneration by local application of lithium: Wnt signal-mediated osteoblastogenesis and Wnt signal-independent suppression of osteoclastogenesis Biochem Pharmacol 2014 90 4 397 405 10.1016/j.bcp.2014.06.011 24955980 Arioka M, Takahashi-Yanaga F, Sasaki M, Yoshihara T, Morimoto S, Hirata M, et al. Acceleration of bone regeneration by local application of lithium: Wnt signal-mediated osteoblastogenesis and Wnt signal-independent suppression of osteoclastogenesis. Biochem Pharmacol. 2014;90(4):397–405. 24955980 10.1016/j.bcp.2014.06.011

Ashrafizadeh M Ahmadi Z Farkhondeh T Samarghandian S Resveratrol targeting the Wnt signaling pathway: A focus on therapeutic activities J Cell Physiol 2020 235 5 4135 4145 10.1002/jcp.29327 31637721 Ashrafizadeh M, Ahmadi Z, Farkhondeh T, Samarghandian S. Resveratrol targeting the Wnt signaling pathway: A focus on therapeutic activities. J Cell Physiol. 2020;235(5):4135–45. 31637721 10.1002/jcp.29327

Ashrafizadeh M Rafiei H Mohammadinejad R Farkhondeh T Samarghandian S Wnt-regulating microRNAs role in gastric cancer malignancy Life Sci 2020 250 117547 10.1016/j.lfs.2020.117547 32173311 Ashrafizadeh M, Rafiei H, Mohammadinejad R, Farkhondeh T, Samarghandian S. Wnt-regulating microRNAs role in gastric cancer malignancy. Life Sci. 2020;250:117547. 32173311 10.1016/j.lfs.2020.117547

Aydin S Kuloglu T Aydin S Kalayci M Yilmaz M Cakmak T A comprehensive immunohistochemical examination of the distribution of the fat-burning protein irisin in biological tissues Peptides 2014 61 130 136 10.1016/j.peptides.2014.09.014 25261800 Aydin S, Kuloglu T, Aydin S, Kalayci M, Yilmaz M, Cakmak T, et al. A comprehensive immunohistochemical examination of the distribution of the fat-burning protein irisin in biological tissues. Peptides. 2014;61:130–6. 25261800 10.1016/j.peptides.2014.09.014

Badimon L Luquero A Crespo J Peña E Borrell-Pages M PCSK9 and LRP5 in macrophage lipid internalization and inflammation Cardiovasc Res 2021 117 9 2054 2068 10.1093/cvr/cvaa254 32991689 Badimon L, Luquero A, Crespo J, Peña E, Borrell-Pages M. PCSK9 and LRP5 in macrophage lipid internalization and inflammation. Cardiovasc Res. 2021;117(9):2054–68. 32991689 10.1093/cvr/cvaa254

Balemans W Van Hul W The genetics of low-density lipoprotein receptor-related protein 5 in bone: a story of extremes Endocrinology 2007 148 6 2622 2629 10.1210/en.2006-1352 17395706 Balemans W, Van Hul W. The genetics of low-density lipoprotein receptor-related protein 5 in bone: a story of extremes. Endocrinology. 2007;148(6):2622–9. 17395706 10.1210/en.2006-1352

Bilic J Huang YL Davidson G Zimmermann T Cruciat CM Bienz M Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation Science 2007 316 5831 1619 1622 10.1126/science.1137065 17569865 Bilic J, Huang YL, Davidson G, Zimmermann T, Cruciat CM, Bienz M, et al. Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science. 2007;316(5831):1619–22. 17569865 10.1126/science.1137065

Boakye YD Agyare C Abotsi WK Ayande PG Ossei PP Anti-inflammatory activity of aqueous leaf extract of Phyllanthus muellerianus (Kuntze) Exell. and its major constituent, geraniin J Ethnopharmacol 2016 187 17 27 10.1016/j.jep.2016.04.020 27103113 Boakye YD, Agyare C, Abotsi WK, Ayande PG, Ossei PP. Anti-inflammatory activity of aqueous leaf extract of Phyllanthus muellerianus (Kuntze) Exell. and its major constituent, geraniin. J Ethnopharmacol. 2016;187:17–27. 27103113 10.1016/j.jep.2016.04.020

Borrell-Pagès M Romero JC Juan-Babot O Badimon L Wnt pathway activation, cell migration, and lipid uptake is regulated by low-density lipoprotein receptor-related protein 5 in human macrophages Eur Heart J 2011 32 22 2841 2850 10.1093/eurheartj/ehr062 21398644 Borrell-Pagès M, Romero JC, Juan-Babot O, Badimon L. Wnt pathway activation, cell migration, and lipid uptake is regulated by low-density lipoprotein receptor-related protein 5 in human macrophages. Eur Heart J. 2011;32(22):2841–50. 21398644 10.1093/eurheartj/ehr062

Cai Z Liu J Bian H Cai J Albiflorin alleviates ovalbumin (OVA)-induced pulmonary inflammation in asthmatic mice Am J Transl Res 2019 11 12 7300 7309 31934279 PMC6943473 Cai Z, Liu J, Bian H, Cai J. Albiflorin alleviates ovalbumin (OVA)-induced pulmonary inflammation in asthmatic mice. Am J Transl Res. 2019;11(12):7300–9. 31934279 PMC6943473

Capurro V Lanfranco M Summa M Porceddu PF Ciampoli M Margaroli N The mood stabilizing properties of AF3581, a novel potent GSK-3β inhibitor Biomed Pharmacother 2020 128 110249 10.1016/j.biopha.2020.110249 32470749 Capurro V, Lanfranco M, Summa M, Porceddu PF, Ciampoli M, Margaroli N, et al. The mood stabilizing properties of AF3581, a novel potent GSK-3β inhibitor. Biomed Pharmacother. 2020;128:110249. 32470749 10.1016/j.biopha.2020.110249

Carrino M Quotti Tubi L Fregnani A Canovas Nunes S Barilà G Trentin L Prosurvival autophagy is regulated by protein kinase CK1 alpha in multiple myeloma Cell Death Discov 2019 5 98 10.1038/s41420-019-0179-1 31123604 PMC6529432 Carrino M, Quotti Tubi L, Fregnani A, Canovas Nunes S, Barilà G, Trentin L, et al. Prosurvival autophagy is regulated by protein kinase CK1 alpha in multiple myeloma. Cell Death Discov. 2019;5:98. 31123604 10.1038/s41420-019-0179-1 PMC6529432

Cederroth CR Auger J Zimmermann C Eustache F Nef S Soy, phyto-oestrogens and male reproductive function: a review Int J Androl 2010 33 2 304 316 10.1111/j.1365-2605.2009.01011.x 19919579 Cederroth CR, Auger J, Zimmermann C, Eustache F, Nef S. Soy, phyto-oestrogens and male reproductive function: a review. Int J Androl. 2010;33(2):304–16. 19919579 10.1111/j.1365-2605.2009.01011.x

Chen S Yang L He S Yang J Liu D Bao Q Preactivation of β-catenin in osteoblasts improves the osteoanabolic effect of PTH in type 1 diabetic mice J Cell Physiol 2020 235 2 1480 1493 10.1002/jcp.29068 31301073 Chen S, Yang L, He S, Yang J, Liu D, Bao Q, et al. Preactivation of β-catenin in osteoblasts improves the osteoanabolic effect of PTH in type 1 diabetic mice. J Cell Physiol. 2020;235(2):1480–93. 31301073 10.1002/jcp.29068

Chen Z Zhang Y Zhao F Yin C Yang C Wang X Recombinant irisin prevents the reduction of osteoblast differentiation induced by stimulated microgravity through increasing β-catenin expression Int J Mol Sci 2020 21 4 1259 10.3390/ijms21041259 32070052 PMC7072919 Chen Z, Zhang Y, Zhao F, Yin C, Yang C, Wang X, et al. Recombinant irisin prevents the reduction of osteoblast differentiation induced by stimulated microgravity through increasing β-catenin expression. Int J Mol Sci. 2020;21(4):1259. 32070052 10.3390/ijms21041259 PMC7072919

Cheng X Wei B Sun L Hu X Liang J Chen Y Astragaloside I stimulates osteoblast differentiation through the Wnt/β-catenin signaling pathway Phytother Res 2016 30 10 1680 1688 10.1002/ptr.5674 27397144 Cheng X, Wei B, Sun L, Hu X, Liang J, Chen Y. Astragaloside I stimulates osteoblast differentiation through the Wnt/β-catenin signaling pathway. Phytother Res. 2016;30(10):1680–8. 27397144 10.1002/ptr.5674

Cheng J Shen W Jin L Pan J Zhou Y Pan G Treadmill exercise promotes neurogenesis and myelin repair via upregulating Wnt/β-catenin signaling pathways in the juvenile brain following focal cerebral ischemia/reperfusion Int J Mol Med 2020 45 5 1447 1463 32323740 10.3892/ijmm.2020.4515 PMC7138282 Cheng J, Shen W, Jin L, Pan J, Zhou Y, Pan G, et al. Treadmill exercise promotes neurogenesis and myelin repair via upregulating Wnt/β-catenin signaling pathways in the juvenile brain following focal cerebral ischemia/reperfusion. Int J Mol Med. 2020;45(5):1447–63. 32323740 10.3892/ijmm.2020.4515 PMC7138282

Cheong JK Virshup DM Casein kinase 1: complexity in the family Int J Biochem Cell Biol 2011 43 4 465 469 10.1016/j.biocel.2010.12.004 21145983 Cheong JK, Virshup DM. Casein kinase 1: complexity in the family. Int J Biochem Cell Biol. 2011;43(4):465–9. 21145983 10.1016/j.biocel.2010.12.004

Chu Y Gao Y Yang Y Liu Y Guo N Wang L β-catenin mediates fluoride-induced aberrant osteoblasts activity and osteogenesis Environ Pollut 2020 265 Pt A 114734 10.1016/j.envpol.2020.114734 32806408 Chu Y, Gao Y, Yang Y, Liu Y, Guo N, Wang L, et al. β-catenin mediates fluoride-induced aberrant osteoblasts activity and osteogenesis. Environ Pollut. 2020;265(Pt A):114734. 32806408 10.1016/j.envpol.2020.114734

Compston JE McClung MR Leslie WD Osteoporosis Lancet 2019 393 10169 364 376 10.1016/S0140-6736(18)32112-3 30696576 Compston JE, McClung MR, Leslie WD. Osteoporosis. Lancet. 2019;393(10169):364–76. 30696576 10.1016/S0140-6736(18)32112-3

Dann CE Hsieh JC Rattner A Sharma D Nathans J Leahy DJ Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains Nature 2001 412 6842 86 90 10.1038/35083601 11452312 Dann CE, Hsieh JC, Rattner A, Sharma D, Nathans J, Leahy DJ. Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains. Nature. 2001;412(6842):86–90. 11452312 10.1038/35083601

Delany AM Amling M Priemel M Howe C Baron R Canalis E Osteopenia and decreased bone formation in osteonectin-deficient mice J Clin Invest 2000 105 7 915 923 10.1172/JCI7039 10749571 PMC377474 Delany AM, Amling M, Priemel M, Howe C, Baron R, Canalis E. Osteopenia and decreased bone formation in osteonectin-deficient mice. J Clin Invest. 2000;105(7):915–23. 10749571 10.1172/JCI7039 PMC377474

Deldar Abad Paskeh M Mirzaei S Ashrafizadeh M Zarrabi A Sethi G Wnt/β-catenin signaling as a driver of hepatocellular carcinoma progression: an emphasis on molecular pathways J Hepatocell Carcinoma 2021 8 1415 1444 10.2147/JHC.S336858 34858888 PMC8630469 Deldar Abad Paskeh M, Mirzaei S, Ashrafizadeh M, Zarrabi A, Sethi G. Wnt/β-catenin signaling as a driver of hepatocellular carcinoma progression: an emphasis on molecular pathways. J Hepatocell Carcinoma. 2021;8:1415–44. 34858888 10.2147/JHC.S336858 PMC8630469

Devalaraja S Jain S Yadav H Exotic fruits as therapeutic complements for diabetes, obesity and metabolic syndrome Food Res Int 2011 44 7 1856 1865 10.1016/j.foodres.2011.04.008 21857774 PMC3156450 Devalaraja S, Jain S, Yadav H. Exotic fruits as therapeutic complements for diabetes, obesity and metabolic syndrome. Food Res Int. 2011;44(7):1856–65. 21857774 10.1016/j.foodres.2011.04.008 PMC3156450

Ding J Lee SJ Vlahos L Yuki K Rada CC van Unen V Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD(4)-selective WNT surrogate in mice Nat Commun 2023 14 1 2947 10.1038/s41467-023-37689-1 37268690 PMC10238527 Ding J, Lee SJ, Vlahos L, Yuki K, Rada CC, van Unen V, et al. Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD(4)-selective WNT surrogate in mice. Nat Commun. 2023;14(1):2947. 37268690 10.1038/s41467-023-37689-1 PMC10238527

Dong B Simonson L Vold S Oldham E Barten L Ahmad N FZD6 promotes melanoma cell invasion but not proliferation by regulating canonical wnt signaling and epithelial-mesenchymal transition J Invest Dermatol 2023 143 4 621 29.e6 10.1016/j.jid.2022.09.658 36368445 PMC10292634 Dong B, Simonson L, Vold S, Oldham E, Barten L, Ahmad N, et al. FZD6 promotes melanoma cell invasion but not proliferation by regulating canonical wnt signaling and epithelial-mesenchymal transition. J Invest Dermatol. 2023;143(4):621-29.e6. 36368445 10.1016/j.jid.2022.09.658 PMC10292634

Du L Nong MN Zhao JM Peng XM Zong SH Zeng GF Polygonatum sibiricum polysaccharide inhibits osteoporosis by promoting osteoblast formation and blocking osteoclastogenesis through Wnt/β-catenin signalling pathway Sci Rep 2016 6 32261 10.1038/srep32261 27554324 PMC4995504 Du L, Nong MN, Zhao JM, Peng XM, Zong SH, Zeng GF. Polygonatum sibiricum polysaccharide inhibits osteoporosis by promoting osteoblast formation and blocking osteoclastogenesis through Wnt/β-catenin signalling pathway. Sci Rep. 2016;6:32261. 27554324 10.1038/srep32261 PMC4995504

Duan J Li H Wang C Yao J Jin Y Zhao J BMSC-derived extracellular vesicles promoted osteogenesis via Axin2 inhibition by delivering MiR-16-5p Int Immunopharmacol 2023 120 110319 10.1016/j.intimp.2023.110319 37216799 Duan J, Li H, Wang C, Yao J, Jin Y, Zhao J, et al. BMSC-derived extracellular vesicles promoted osteogenesis via Axin2 inhibition by delivering MiR-16-5p. Int Immunopharmacol. 2023;120:110319. 37216799 10.1016/j.intimp.2023.110319

Duker-Eshun G Jaroszewski JW Asomaning WA Oppong-Boachie F Brøgger CS Antiplasmodial constituents of Cajanus cajan Phytother Res 2004 18 2 128 130 10.1002/ptr.1375 15022164 Duker-Eshun G, Jaroszewski JW, Asomaning WA, Oppong-Boachie F, Brøgger CS. Antiplasmodial constituents of Cajanus cajan. Phytother Res. 2004;18(2):128–30. 15022164 10.1002/ptr.1375

Dun SL Lyu RM Chen YH Chang JK Luo JJ Dun NJ Irisin-immunoreactivity in neural and non-neural cells of the rodent Neuroscience 2013 240 155 162 10.1016/j.neuroscience.2013.02.050 23470775 PMC3637839 Dun SL, Lyu RM, Chen YH, Chang JK, Luo JJ, Dun NJ. Irisin-immunoreactivity in neural and non-neural cells of the rodent. Neuroscience. 2013;240:155–62. 23470775 10.1016/j.neuroscience.2013.02.050 PMC3637839

Elendran S Wang LW Prankerd R Palanisamy UD The physicochemical properties of geraniin, a potential antihyperglycemic agent Pharm Biol 2015 53 12 1719 1726 10.3109/13880209.2014.1003356 25853977 Elendran S, Wang LW, Prankerd R, Palanisamy UD. The physicochemical properties of geraniin, a potential antihyperglycemic agent. Pharm Biol. 2015;53(12):1719–26. 25853977 10.3109/13880209.2014.1003356

Gambardella A Nagaraju CK O'Shea PJ Mohanty ST Kottam L Pilling J Glycogen synthase kinase-3α/β inhibition promotes in vivo amplification of endogenous mesenchymal progenitors with osteogenic and adipogenic potential and their differentiation to the osteogenic lineage J Bone Miner Res 2011 26 4 811 821 10.1002/jbmr.266 20939016 Gambardella A, Nagaraju CK, O’Shea PJ, Mohanty ST, Kottam L, Pilling J, et al. Glycogen synthase kinase-3α/β inhibition promotes in vivo amplification of endogenous mesenchymal progenitors with osteogenic and adipogenic potential and their differentiation to the osteogenic lineage. J Bone Miner Res. 2011;26(4):811–21. 20939016 10.1002/jbmr.266

Gan XQ Wang JY Xi Y Wu ZL Li YP Li L Nuclear Dvl, c-Jun, beta-catenin, and TCF form a complex leading to stabilization of beta-catenin-TCF interaction J Cell Biol 2008 180 6 1087 1100 10.1083/jcb.200710050 18347071 PMC2290839 Gan XQ, Wang JY, Xi Y, Wu ZL, Li YP, Li L. Nuclear Dvl, c-Jun, beta-catenin, and TCF form a complex leading to stabilization of beta-catenin-TCF interaction. J Cell Biol. 2008;180(6):1087–100. 18347071 10.1083/jcb.200710050 PMC2290839

Ge J Yu YJ Li JY Li MY Xia SM Xue K Activating Wnt/β-catenin signaling by autophagic degradation of APC contributes to the osteoblast differentiation effect of soy isoflavone on osteoporotic mesenchymal stem cells Acta Pharmacol Sin 2023 44 9 1841 1855 10.1038/s41401-023-01066-x 36973541 PMC10462682 Ge J, Yu YJ, Li JY, Li MY, Xia SM, Xue K, et al. Activating Wnt/β-catenin signaling by autophagic degradation of APC contributes to the osteoblast differentiation effect of soy isoflavone on osteoporotic mesenchymal stem cells. Acta Pharmacol Sin. 2023;44(9):1841–55. 36973541 10.1038/s41401-023-01066-x PMC10462682

Graham TA Weaver C Mao F Kimelman D Xu W Crystal structure of a beta-catenin/Tcf complex Cell 2000 103 6 885 896 10.1016/S0092-8674(00)00192-6 11136974 Graham TA, Weaver C, Mao F, Kimelman D, Xu W. Crystal structure of a beta-catenin/Tcf complex. Cell. 2000;103(6):885–96. 11136974 10.1016/s0092-8674(00)00192-6

Guil-Luna S Rivas-Crespo A Navarrete-Sirvent C Mantrana A Pera A Mena-Osuna R Clinical significance of glycogen synthase kinase 3 (GSK-3) expression and tumor budding grade in colorectal cancer: Implications for targeted therapy Biomed Pharmacother 2023 167 115592 10.1016/j.biopha.2023.115592 37778272 Guil-Luna S, Rivas-Crespo A, Navarrete-Sirvent C, Mantrana A, Pera A, Mena-Osuna R, et al. Clinical significance of glycogen synthase kinase 3 (GSK-3) expression and tumor budding grade in colorectal cancer: Implications for targeted therapy. Biomed Pharmacother. 2023;167:115592. 37778272 10.1016/j.biopha.2023.115592

Gupta A Chatree S Buo AM Moorer MC Stains JP Connexin43 enhances Wnt and PGE2-dependent activation of β-catenin in osteoblasts Pflugers Arch 2019 471 9 1235 1243 10.1007/s00424-019-02295-y 31240382 PMC6711805 Gupta A, Chatree S, Buo AM, Moorer MC, Stains JP. Connexin43 enhances Wnt and PGE2-dependent activation of β-catenin in osteoblasts. Pflugers Arch. 2019;471(9):1235–43. 31240382 10.1007/s00424-019-02295-y PMC6711805

He J Li X Wang Z Bennett S Chen K Xiao Z Therapeutic anabolic and anticatabolic benefits of natural chinese medicines for the treatment of osteoporosis Front Pharmacol 2019 10 1344 10.3389/fphar.2019.01344 31824310 PMC6886594 He J, Li X, Wang Z, Bennett S, Chen K, Xiao Z, et al. Therapeutic anabolic and anticatabolic benefits of natural chinese medicines for the treatment of osteoporosis. Front Pharmacol. 2019;10:1344. 31824310 10.3389/fphar.2019.01344 PMC6886594

He X Cheng R Huang C Takahashi Y Yang Y Benyajati S A novel role of LRP5 in tubulointerstitial fibrosis through activating TGF-β/Smad signaling Signal Transduct Target Ther 2020 5 1 45 10.1038/s41392-020-0142-x 32345960 PMC7188863 He X, Cheng R, Huang C, Takahashi Y, Yang Y, Benyajati S, et al. A novel role of LRP5 in tubulointerstitial fibrosis through activating TGF-β/Smad signaling. Signal Transduct Target Ther. 2020;5(1):45. 32345960 10.1038/s41392-020-0142-x PMC7188863

He J Nascakova Z Leary P Papa G Valenta T Basler K Inactivation of the tumor suppressor gene Apc synergizes with H. pylori to induce DNA damage in murine gastric stem and progenitor cells Sci Adv 2023 9 46 eadh0322 10.1126/sciadv.adh0322 37967175 PMC10651120 He J, Nascakova Z, Leary P, Papa G, Valenta T, Basler K, et al. Inactivation of the tumor suppressor gene Apc synergizes with H. pylori to induce DNA damage in murine gastric stem and progenitor cells. Sci Adv. 2023;9(46):eadh0322. 37967175 10.1126/sciadv.adh0322 PMC10651120

Hill TP Später D Taketo MM Birchmeier W Hartmann C Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes Dev Cell 2005 8 5 727 738 10.1016/j.devcel.2005.02.013 15866163 Hill TP, Später D, Taketo MM, Birchmeier W, Hartmann C. Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell. 2005;8(5):727–38. 15866163 10.1016/j.devcel.2005.02.013

Hiremath IS Goel A Warrier S Kumar AP Sethi G Garg M The multidimensional role of the Wnt/β-catenin signaling pathway in human malignancies J Cell Physiol 2022 237 1 199 238 10.1002/jcp.30561 34431086 Hiremath IS, Goel A, Warrier S, Kumar AP, Sethi G, Garg M. The multidimensional role of the Wnt/β-catenin signaling pathway in human malignancies. J Cell Physiol. 2022;237(1):199–238. 34431086 10.1002/jcp.30561

Hofbauer LC Maisch B Schaefer JR High bone density due to a mutation in LDL-receptor-related protein 5 N Engl J Med 2002 347 12 943 944 10.1056/NEJM200209193471216 12240686 Hofbauer LC, Maisch B, Schaefer JR. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002;347(12):943–4. 12240686

Hsu W Zeng L Costantini F Identification of a domain of Axin that binds to the serine/threonine protein phosphatase 2A and a self-binding domain J Biol Chem 1999 274 6 3439 3445 10.1074/jbc.274.6.3439 9920888 Hsu W, Zeng L, Costantini F. Identification of a domain of Axin that binds to the serine/threonine protein phosphatase 2A and a self-binding domain. J Biol Chem. 1999;274(6):3439–45. 9920888 10.1074/jbc.274.6.3439

Hua H Su T Han L Zhang L Huang Y Zhang N LINC01226 promotes gastric cancer progression through enhancing cytoplasm-to-nucleus translocation of STIP1 and stabilizing β-catenin protein Cancer Lett 2023 577 216436 10.1016/j.canlet.2023.216436 37806517 Hua H, Su T, Han L, Zhang L, Huang Y, Zhang N, et al. LINC01226 promotes gastric cancer progression through enhancing cytoplasm-to-nucleus translocation of STIP1 and stabilizing β-catenin protein. Cancer Lett. 2023;577:216436. 37806517 10.1016/j.canlet.2023.216436

Huang HC Klein PS The Frizzled family: receptors for multiple signal transduction pathways Genome Biol 2004 5 7 234 10.1186/gb-2004-5-7-234 15239825 PMC463283 Huang HC, Klein PS. The Frizzled family: receptors for multiple signal transduction pathways. Genome Biol. 2004;5(7):234. 15239825 10.1186/gb-2004-5-7-234 PMC463283

Huang TX Tan XY Huang HS Li YT Liu BL Liu KS Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity Gut 2022 71 2 333 344 10.1136/gutjnl-2020-322924 33692094 PMC8762012 Huang TX, Tan XY, Huang HS, Li YT, Liu BL, Liu KS, et al. Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity. Gut. 2022;71(2):333–44. 33692094 10.1136/gutjnl-2020-322924 PMC8762012

Huo L Jiang Z Lei M Wang X Guo X Simultaneous quantification of Kirenol and ent-16β,17-dihydroxy-kauran-19-oic acid from Herba Siegesbeckiae in rat plasma by liquid chromatography-tandem mass spectrometry and its application to pharmacokinetic studies J Chromatogr B Analyt Technol Biomed Life Sci 2013 937 18 24 10.1016/j.jchromb.2013.08.019 24008120 Huo L, Jiang Z, Lei M, Wang X, Guo X. Simultaneous quantification of Kirenol and ent-16β,17-dihydroxy-kauran-19-oic acid from Herba Siegesbeckiae in rat plasma by liquid chromatography-tandem mass spectrometry and its application to pharmacokinetic studies. J Chromatogr B Analyt Technol Biomed Life Sci. 2013;937:18–24. 24008120 10.1016/j.jchromb.2013.08.019

Hwang JH Cha PH Han G Bach TT Min JH Choi JH Euodia sutchuenensis Dode extract stimulates osteoblast differentiation via Wnt/β-catenin pathway activation Exp Mol Med 2015 47 3 e152 10.1038/emm.2014.115 25792220 PMC4351407 Hwang JH, Cha PH, Han G, Bach TT, Min JH, Choi JH. Euodia sutchuenensis Dode extract stimulates osteoblast differentiation via Wnt/β-catenin pathway activation. Exp Mol Med. 2015;47(3):e152. 25792220 10.1038/emm.2014.115 PMC4351407

Jaiswal AS Multani AS Pathak S Narayan S N-methyl-N'-nitro-N-nitrosoguanidine-induced senescence-like growth arrest in colon cancer cells is associated with loss of adenomatous polyposis coli protein, microtubule organization, and telomeric DNA Mol Cancer 2004 3 3 10.1186/1476-4598-3-3 14728717 PMC320492 Jaiswal AS, Multani AS, Pathak S, Narayan S. N-methyl-N’-nitro-N-nitrosoguanidine-induced senescence-like growth arrest in colon cancer cells is associated with loss of adenomatous polyposis coli protein, microtubule organization, and telomeric DNA. Mol Cancer. 2004;3:3. 14728717 10.1186/1476-4598-3-3 PMC320492

Jeong W Jho EH Regulation of the low-density lipoprotein receptor-related protein LRP6 and its association with disease: Wnt/β-catenin signaling and beyond Front Cell Dev Biol 2021 9 714330 10.3389/fcell.2021.714330 34589484 PMC8473786 Jeong W, Jho EH. Regulation of the low-density lipoprotein receptor-related protein LRP6 and its association with disease: Wnt/β-catenin signaling and beyond. Front Cell Dev Biol. 2021;9:714330. 34589484 10.3389/fcell.2021.714330 PMC8473786

Jiang Z Yu QH Cheng Y Guo XJ Simultaneous quantification of eight major constituents in Herba Siegesbeckiae by liquid chromatography coupled with electrospray ionization time-of-flight tandem mass spectrometry J Pharm Biomed Anal 2011 55 3 452 457 10.1016/j.jpba.2011.02.023 21411260 Jiang Z, Yu QH, Cheng Y, Guo XJ. Simultaneous quantification of eight major constituents in Herba Siegesbeckiae by liquid chromatography coupled with electrospray ionization time-of-flight tandem mass spectrometry. J Pharm Biomed Anal. 2011;55(3):452–7. 21411260 10.1016/j.jpba.2011.02.023

Jones C Avino M Giroux V Boudreau F HNF4α acts as upstream functional regulator of intestinal Wnt3 and paneth cell fate Cell Mol Gastroenterol Hepatol 2023 15 3 593 612 10.1016/j.jcmgh.2022.11.010 36464209 PMC9871320 Jones C, Avino M, Giroux V, Boudreau F. HNF4α acts as upstream functional regulator of intestinal Wnt3 and paneth cell fate. Cell Mol Gastroenterol Hepatol. 2023;15(3):593–612. 36464209 10.1016/j.jcmgh.2022.11.010 PMC9871320

Jung YY Ko JH Um JY Sethi G Ahn KS A novel role of bergamottin in attenuating cancer associated cachexia by diverse molecular mechanisms Cancers 2021 13 6 1347 10.3390/cancers13061347 33802674 PMC8002497 Jung YY, Ko JH, Um JY, Sethi G, Ahn KS. A novel role of bergamottin in attenuating cancer associated cachexia by diverse molecular mechanisms. Cancers. 2021;13(6):1347. 33802674 10.3390/cancers13061347 PMC8002497

Kaplan KB Burds AA Swedlow JR Bekir SS Sorger PK Näthke IS A role for the adenomatous polyposis coli protein in chromosome segregation Nat Cell Biol 2001 3 4 429 432 10.1038/35070123 11283619 Kaplan KB, Burds AA, Swedlow JR, Bekir SS, Sorger PK, Näthke IS. A role for the adenomatous polyposis coli protein in chromosome segregation. Nat Cell Biol. 2001;3(4):429–32. 11283619 10.1038/35070123

Karadeniz F Oh JH Lee JI Seo Y Kong CS 3,5-dicaffeoyl-epi-quinic acid from Atriplex gmelinii enhances the osteoblast differentiation of bone marrow-derived human mesenchymal stromal cells via WnT/BMP signaling and suppresses adipocyte differentiation via AMPK activation Phytomedicine 2020 71 153225 10.1016/j.phymed.2020.153225 32464299 Karadeniz F, Oh JH, Lee JI, Seo Y, Kong CS. 3,5-dicaffeoyl-epi-quinic acid from Atriplex gmelinii enhances the osteoblast differentiation of bone marrow-derived human mesenchymal stromal cells via WnT/BMP signaling and suppresses adipocyte differentiation via AMPK activation. Phytomedicine. 2020;71:153225. 32464299 10.1016/j.phymed.2020.153225

Kim MB Song Y Hwang JK Kirenol stimulates osteoblast differentiation through activation of the BMP and Wnt/β-catenin signaling pathways in MC3T3-E1 cells Fitoterapia 2014 98 59 65 10.1016/j.fitote.2014.07.013 25062891 Kim MB, Song Y, Hwang JK. Kirenol stimulates osteoblast differentiation through activation of the BMP and Wnt/β-catenin signaling pathways in MC3T3-E1 cells. Fitoterapia. 2014;98:59–65. 25062891 10.1016/j.fitote.2014.07.013

Kim HY Yoon JY Yun JH Cho KW Lee SH Rhee YM CXXC5 is a negative-feedback regulator of the Wnt/β-catenin pathway involved in osteoblast differentiation Cell Death Differ 2015 22 6 912 920 10.1038/cdd.2014.238 25633194 PMC4423189 Kim HY, Yoon JY, Yun JH, Cho KW, Lee SH, Rhee YM, et al. CXXC5 is a negative-feedback regulator of the Wnt/β-catenin pathway involved in osteoblast differentiation. Cell Death Differ. 2015;22(6):912–20. 25633194 10.1038/cdd.2014.238 PMC4423189

Kim JH Kim M Hong S Kim EY Lee H Jung HS Albiflorin promotes osteoblast differentiation and healing of rat femoral fractures through enhancing BMP-2/Smad and Wnt/β-catenin signaling Front Pharmacol 2021 12 690113 10.3389/fphar.2021.690113 34349649 PMC8327266 Kim JH, Kim M, Hong S, Kim EY, Lee H, Jung HS, et al. Albiflorin promotes osteoblast differentiation and healing of rat femoral fractures through enhancing BMP-2/Smad and Wnt/β-catenin signaling. Front Pharmacol. 2021;12:690113. 34349649 10.3389/fphar.2021.690113 PMC8327266

Kimelman D Xu W beta-catenin destruction complex: insights and questions from a structural perspective Oncogene 2006 25 57 7482 7491 10.1038/sj.onc.1210055 17143292 Kimelman D, Xu W. beta-catenin destruction complex: insights and questions from a structural perspective. Oncogene. 2006;25(57):7482–91. 17143292 10.1038/sj.onc.1210055

Knippschild U Gocht A Wolff S Huber N Löhler J Stöter M The casein kinase 1 family: participation in multiple cellular processes in eukaryotes Cell Signal 2005 17 6 675 689 10.1016/j.cellsig.2004.12.011 15722192 Knippschild U, Gocht A, Wolff S, Huber N, Löhler J, Stöter M. The casein kinase 1 family: participation in multiple cellular processes in eukaryotes. Cell Signal. 2005;17(6):675–89. 15722192 10.1016/j.cellsig.2004.12.011

Ko JH Nam D Um JY Jung SH Ahn KS Bergamottin inhibits adipogenesis in 3T3-L1 cells and weight regulation in diet-induced obese mice Am J Chin Med 2018 46 3 601 615 10.1142/S0192415X18500313 29614883 Ko JH, Nam D, Um JY, Jung SH, Ahn KS. Bergamottin inhibits adipogenesis in 3T3-L1 cells and weight regulation in diet-induced obese mice. Am J Chin Med. 2018;46(3):601–15. 29614883 10.1142/S0192415X18500313

Koyama-Nasu R Hayashi T Nasu-Nishimura Y Akiyama T Yamanaka R Thr160 of Axin1 is critical for the formation and function of the β-catenin destruction complex Biochem Biophys Res Commun 2015 459 3 411 415 10.1016/j.bbrc.2015.02.118 25735981 Koyama-Nasu R, Hayashi T, Nasu-Nishimura Y, Akiyama T, Yamanaka R. Thr160 of Axin1 is critical for the formation and function of the β-catenin destruction complex. Biochem Biophys Res Commun. 2015;459(3):411–5. 25735981 10.1016/j.bbrc.2015.02.118

Kushwaha P Kim S Foxa GE Michalski MN Williams BO Tomlinson RE Frizzled-4 is required for normal bone acquisition despite compensation by Frizzled-8 J Cell Physiol 2020 235 10 6673 6683 10.1002/jcp.29563 31985040 PMC7382978 Kushwaha P, Kim S, Foxa GE, Michalski MN, Williams BO, Tomlinson RE, et al. Frizzled-4 is required for normal bone acquisition despite compensation by Frizzled-8. J Cell Physiol. 2020;235(10):6673–83. 31985040 10.1002/jcp.29563 PMC7382978

Lamien-Meda A Lukas B Schmiderer C Franz C Novak J Validation of a quantitative assay of arbutin using gas chromatography in Origanum majorana and Arctostaphylos uva-ursi extracts Phytochem Anal 2009 20 5 416 420 10.1002/pca.1142 19609883 Lamien-Meda A, Lukas B, Schmiderer C, Franz C, Novak J. Validation of a quantitative assay of arbutin using gas chromatography in Origanum majorana and Arctostaphylos uva-ursi extracts. Phytochem Anal. 2009;20(5):416–20. 19609883 10.1002/pca.1142

Lawson LY Brodt MD Migotsky N Chermside-Scabbo CJ Palaniappan R Silva MJ Osteoblast-specific Wnt secretion is required for skeletal homeostasis and loading-induced bone formation in adult mice J Bone Miner Res 2022 37 1 108 120 10.1002/jbmr.4445 34542191 PMC8770559 Lawson LY, Brodt MD, Migotsky N, Chermside-Scabbo CJ, Palaniappan R, Silva MJ. Osteoblast-specific Wnt secretion is required for skeletal homeostasis and loading-induced bone formation in adult mice. J Bone Miner Res. 2022;37(1):108–20. 34542191 10.1002/jbmr.4445 PMC8770559

Leanza G Fontana F Lee SY Remedi MS Schott C Ferron M Gain-of-function Lrp5 mutation improves bone mass and strength and delays hyperglycemia in a mouse model of insulin-deficient diabetes J Bone Miner Res 2021 36 7 1403 1415 10.1002/jbmr.4303 33831261 PMC8360087 Leanza G, Fontana F, Lee SY, Remedi MS, Schott C, Ferron M, et al. Gain-of-function Lrp5 mutation improves bone mass and strength and delays hyperglycemia in a mouse model of insulin-deficient diabetes. J Bone Miner Res. 2021;36(7):1403–15. 33831261 10.1002/jbmr.4303 PMC8360087

Li K Zhang X He B Yang R Zhang Y Shen Z Geraniin promotes osteoblast proliferation and differentiation via the activation of Wnt/β-catenin pathway Biomed Pharmacother 2018 99 319 324 10.1016/j.biopha.2018.01.040 29353207 Li K, Zhang X, He B, Yang R, Zhang Y, Shen Z, et al. Geraniin promotes osteoblast proliferation and differentiation via the activation of Wnt/β-catenin pathway. Biomed Pharmacother. 2018;99:319–24. 29353207 10.1016/j.biopha.2018.01.040

Li H Zhou W Sun S Zhang T Zhang T Huang H Microfibrillar-associated protein 5 regulates osteogenic differentiation by modulating the Wnt/β-catenin and AMPK signaling pathways Mol Med 2021 27 1 153 10.1186/s10020-021-00413-0 34865619 PMC8647299 Li H, Zhou W, Sun S, Zhang T, Zhang T, Huang H, et al. Microfibrillar-associated protein 5 regulates osteogenic differentiation by modulating the Wnt/β-catenin and AMPK signaling pathways. Mol Med. 2021;27(1):153. 34865619 10.1186/s10020-021-00413-0 PMC8647299

Li W Han Q Zhu Y Zhou Y Zhang J Wu W SUMOylation of RNF146 results in Axin degradation and activation of Wnt/β-catenin signaling to promote the progression of hepatocellular carcinoma Oncogene 2023 42 21 1728 1740 10.1038/s41388-023-02689-4 37029301 Li W, Han Q, Zhu Y, Zhou Y, Zhang J, Wu W, et al. SUMOylation of RNF146 results in Axin degradation and activation of Wnt/β-catenin signaling to promote the progression of hepatocellular carcinoma. Oncogene. 2023;42(21):1728–40. 37029301 10.1038/s41388-023-02689-4

Lim YJ Lee EH Kang TH Ha SK Oh MS Kim SM Inhibitory effects of arbutin on melanin biosynthesis of alpha-melanocyte stimulating hormone-induced hyperpigmentation in cultured brownish guinea pig skin tissues Arch Pharm Res 2009 32 3 367 373 10.1007/s12272-009-1309-8 19387580 Lim YJ, Lee EH, Kang TH, Ha SK, Oh MS, Kim SM, et al. Inhibitory effects of arbutin on melanin biosynthesis of alpha-melanocyte stimulating hormone-induced hyperpigmentation in cultured brownish guinea pig skin tissues. Arch Pharm Res. 2009;32(3):367–73. 19387580 10.1007/s12272-009-1309-8

Lin L Li L Ma G Kang Y Wang X He J Overexpression of IL-8 and Wnt2 is associated with prognosis of gastric cancer Folia Histochem Cytobiol 2022 60 1 66 73 10.5603/FHC.a2022.0002 35037695 Lin L, Li L, Ma G, Kang Y, Wang X, He J. Overexpression of IL-8 and Wnt2 is associated with prognosis of gastric cancer. Folia Histochem Cytobiol. 2022;60(1):66–73. 35037695 10.5603/FHC.a2022.0002

Lin W Chow SKH Cui C Liu C Wang Q Chai S Wnt/β-catenin signaling pathway as an important mediator in muscle and bone crosstalk: a systematic review J Orthop Translat 2024 47 63 73 10.1016/j.jot.2024.06.003 39007034 PMC11245956 Lin W, Chow SKH, Cui C, Liu C, Wang Q, Chai S, et al. Wnt/β-catenin signaling pathway as an important mediator in muscle and bone crosstalk: a systematic review. J Orthop Translat. 2024;47:63–73. 39007034 10.1016/j.jot.2024.06.003 PMC11245956

Liu C Cai D Zhang L Tang W Yan R Guo H Identification of hydrolyzable tannins (punicalagin, punicalin and geraniin) as novel inhibitors of hepatitis B virus covalently closed circular DNA Antiviral Res 2016 134 97 107 10.1016/j.antiviral.2016.08.026 27591143 PMC5653380 Liu C, Cai D, Zhang L, Tang W, Yan R, Guo H, et al. Identification of hydrolyzable tannins (punicalagin, punicalin and geraniin) as novel inhibitors of hepatitis B virus covalently closed circular DNA. Antiviral Res. 2016;134:97–107. 27591143 10.1016/j.antiviral.2016.08.026 PMC5653380

Liu S Luo ZH Ji GM Guo W Cai JZ Fu LC Cajanolactone A from cajanus cajan promoted osteoblast differentiation in human bone marrow mesenchymal stem cells via stimulating Wnt/LRP5/β-catenin signaling Molecules 2019 24 2 271 10.3390/molecules24020271 30642055 PMC6358999 Liu S, Luo ZH, Ji GM, Guo W, Cai JZ, Fu LC, et al. Cajanolactone A from cajanus cajan promoted osteoblast differentiation in human bone marrow mesenchymal stem cells via stimulating Wnt/LRP5/β-catenin signaling. Molecules. 2019;24(2):271. 30642055 10.3390/molecules24020271 PMC6358999

Liu L Liu W Shi Y Li L Gao Y Lei Y DVL mutations identified from human neural tube defects and Dandy-Walker malformation obstruct the Wnt signaling pathway J Genet Genomics 2020 47 6 301 310 10.1016/j.jgg.2020.06.003 32900645 Liu L, Liu W, Shi Y, Li L, Gao Y, Lei Y, et al. DVL mutations identified from human neural tube defects and Dandy-Walker malformation obstruct the Wnt signaling pathway. J Genet Genomics. 2020;47(6):301–10. 32900645 10.1016/j.jgg.2020.06.003

Liu H Zhang L Wang Y Wu R Shen C Li G High Wnt2 expression confers poor prognosis in colorectal cancer, and represents a novel therapeutic target in BRAF-mutated colorectal cancer Medicina (Kaunas) 2023 59 6 1133 10.3390/medicina59061133 37374338 PMC10301164 Liu H, Zhang L, Wang Y, Wu R, Shen C, Li G, et al. High Wnt2 expression confers poor prognosis in colorectal cancer, and represents a novel therapeutic target in BRAF-mutated colorectal cancer. Medicina (Kaunas). 2023a;59(6):1133. 37374338 10.3390/medicina59061133 PMC10301164

Liu J Liu K Chai S Xu R Wang Y Zhang Y Chronic GPER activation prompted the proliferation of ileal stem cell in ovariectomized mice depending on Paneth cell-derived Wnt3 Clin Sci (Lond) 2023 137 1 109 127 10.1042/CS20220392 36503938 Liu J, Liu K, Chai S, Xu R, Wang Y, Zhang Y, et al. Chronic GPER activation prompted the proliferation of ileal stem cell in ovariectomized mice depending on Paneth cell-derived Wnt3. Clin Sci (Lond). 2023b;137(1):109–27. 36503938 10.1042/CS20220392

Lu P Yang J Li M Wen S Zhang T Yan C A desert lncRNA HIDEN regulates human endoderm differentiation via interacting with IMP1 and stabilizing FZD5 mRNA Genome Biol 2023 24 1 92 10.1186/s13059-023-02925-w 37095549 PMC10124006 Lu P, Yang J, Li M, Wen S, Zhang T, Yan C, et al. A desert lncRNA HIDEN regulates human endoderm differentiation via interacting with IMP1 and stabilizing FZD5 mRNA. Genome Biol. 2023;24(1):92. 37095549 10.1186/s13059-023-02925-w PMC10124006

Ma S Wang DD Ma CY Zhang YD microRNA-96 promotes osteoblast differentiation and bone formation in ankylosing spondylitis mice through activating the Wnt signaling pathway by binding to SOST J Cell Biochem 2019 120 9 15429 15442 10.1002/jcb.28810 31111563 Ma S, Wang DD, Ma CY, Zhang YD. microRNA-96 promotes osteoblast differentiation and bone formation in ankylosing spondylitis mice through activating the Wnt signaling pathway by binding to SOST. J Cell Biochem. 2019;120(9):15429–42. 31111563 10.1002/jcb.28810

Man X Yang L Liu S Yang L Li M Fu Q Arbutin promotes MC3T3-E1 mouse osteoblast precursor cell proliferation and differentiation via the Wnt/β-catenin signaling pathway Mol Med Rep 2019 19 6 4637 4644 30957189 10.3892/mmr.2019.10125 PMC6522801 Man X, Yang L, Liu S, Yang L, Li M, Fu Q. Arbutin promotes MC3T3-E1 mouse osteoblast precursor cell proliferation and differentiation via the Wnt/β-catenin signaling pathway. Mol Med Rep. 2019;19(6):4637–44. 30957189 10.3892/mmr.2019.10125 PMC6522801

Martínez-Reina J Calvo-Gallego JL Pivonka P Combined effects of exercise and denosumab treatment on local failure in post-menopausal osteoporosis-insights from bone remodelling simulations accounting for mineralisation and damage Front Bioeng Biotechnol 2021 9 635056 10.3389/fbioe.2021.635056 34150724 PMC8212042 Martínez-Reina J, Calvo-Gallego JL, Pivonka P. Combined effects of exercise and denosumab treatment on local failure in post-menopausal osteoporosis-insights from bone remodelling simulations accounting for mineralisation and damage. Front Bioeng Biotechnol. 2021;9:635056. 34150724 10.3389/fbioe.2021.635056 PMC8212042

Matsumoto Y La Rose J Lim M Adissu HA Law N Mao X Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism J Clin Invest 2017 127 7 2612 2625 10.1172/JCI92233 28581440 PMC5490759 Matsumoto Y, La Rose J, Lim M, Adissu HA, Law N, Mao X, et al. Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism. J Clin Invest. 2017;127(7):2612–25. 28581440 10.1172/JCI92233 PMC5490759

Miclea RL van der Horst G Robanus-Maandag EC Löwik CW Oostdijk W Wit JM Apc bridges Wnt/β-catenin and BMP signaling during osteoblast differentiation of KS483 cells Exp Cell Res 2011 317 10 1411 1421 10.1016/j.yexcr.2011.03.007 21402068 Miclea RL, van der Horst G, Robanus-Maandag EC, Löwik CW, Oostdijk W, Wit JM, et al. Apc bridges Wnt/β-catenin and BMP signaling during osteoblast differentiation of KS483 cells. Exp Cell Res. 2011;317(10):1411–21. 21402068 10.1016/j.yexcr.2011.03.007

Mohn JL Alexander J Pirone A Palka CD Lee SY Mebane L Adenomatous polyposis coli protein deletion leads to cognitive and autism-like disabilities Mol Psychiatry 2014 19 10 1133 1142 10.1038/mp.2014.61 24934177 PMC4317257 Mohn JL, Alexander J, Pirone A, Palka CD, Lee SY, Mebane L, et al. Adenomatous polyposis coli protein deletion leads to cognitive and autism-like disabilities. Mol Psychiatry. 2014;19(10):1133–42. 24934177 10.1038/mp.2014.61 PMC4317257

Molagoda IMN Karunarathne W Choi YH Park EK Jeon YJ Lee BJ Fermented oyster extract promotes osteoblast differentiation by activating the Wnt/β-catenin signaling pathway, leading to bone formation Biomolecule 2019 9 11 711 10.3390/biom9110711 PMC6920898 31698882 Molagoda IMN, Karunarathne W, Choi YH, Park EK, Jeon YJ, Lee BJ, et al. Fermented oyster extract promotes osteoblast differentiation by activating the Wnt/β-catenin signaling pathway, leading to bone formation. Biomolecule. 2019;9(11):711. 10.3390/biom9110711 PMC6920898 31698882

Moosa S Yamamoto GL Garbes L Keupp K Beleza-Meireles A Moreno CA Autosomal-recessive mutations in MESD cause osteogenesis imperfecta Am J Hum Genet 2019 105 4 836 843 10.1016/j.ajhg.2019.08.008 31564437 PMC6817720 Moosa S, Yamamoto GL, Garbes L, Keupp K, Beleza-Meireles A, Moreno CA, et al. Autosomal-recessive mutations in MESD cause osteogenesis imperfecta. Am J Hum Genet. 2019;105(4):836–43. 31564437 10.1016/j.ajhg.2019.08.008 PMC6817720

Nichols SA Roberts BW Richter DJ Fairclough SR King N Origin of metazoan cadherin diversity and the antiquity of the classical cadherin/β-catenin complex Proc Natl Acad Sci U S A 2012 109 32 13046 13051 10.1073/pnas.1120685109 22837400 PMC3420208 Nichols SA, Roberts BW, Richter DJ, Fairclough SR, King N. Origin of metazoan cadherin diversity and the antiquity of the classical cadherin/β-catenin complex. Proc Natl Acad Sci U S A. 2012;109(32):13046–51. 22837400 10.1073/pnas.1120685109 PMC3420208

Niemann S Zhao C Pascu F Stahl U Aulepp U Niswander L Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family Am J Hum Genet 2004 74 3 558 563 10.1086/382196 14872406 PMC1182269 Niemann S, Zhao C, Pascu F, Stahl U, Aulepp U, Niswander L, et al. Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family. Am J Hum Genet. 2004;74(3):558–63. 14872406 10.1086/382196 PMC1182269

Nusse R Clevers H Wnt/β-catenin signaling, disease, and emerging therapeutic modalities Cell 2017 169 6 985 999 10.1016/j.cell.2017.05.016 28575679 Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169(6):985–99. 28575679 10.1016/j.cell.2017.05.016

Pai VC Hsu CC Chan TS Liao WY Chuu CP Chen WY ASPM promotes prostate cancer stemness and progression by augmenting Wnt-Dvl-3-β-catenin signaling Oncogene 2019 38 8 1340 1353 10.1038/s41388-018-0497-4 30266990 Pai VC, Hsu CC, Chan TS, Liao WY, Chuu CP, Chen WY, et al. ASPM promotes prostate cancer stemness and progression by augmenting Wnt-Dvl-3-β-catenin signaling. Oncogene. 2019;38(8):1340–53. 30266990 10.1038/s41388-018-0497-4

Patel JR Tripathi P Sharma V Chauhan NS Dixit VK Phyllanthus amarus: ethnomedicinal uses, phytochemistry and pharmacology: a review J Ethnopharmacol 2011 138 2 286 313 10.1016/j.jep.2011.09.040 21982793 Patel JR, Tripathi P, Sharma V, Chauhan NS, Dixit VK. Phyllanthus amarus: ethnomedicinal uses, phytochemistry and pharmacology: a review. J Ethnopharmacol. 2011;138(2):286–313. 21982793 10.1016/j.jep.2011.09.040

Pietrus M Pitynski K Waligora M Milian-Ciesielska K Ludwin A Socha MW Association of membranous WNT-1 and nuclear mTOR with endometrial cancer grade Int J Mol Sci 2023 24 9 8342 10.3390/ijms24098342 37176048 PMC10179139 Pietrus M, Pitynski K, Waligora M, Milian-Ciesielska K, Ludwin A, Socha MW, et al. Association of membranous WNT-1 and nuclear mTOR with endometrial cancer grade. Int J Mol Sci. 2023;24(9):8342. 37176048 10.3390/ijms24098342 PMC10179139

Ponzetti M Rucci N Osteoblast differentiation and signaling: established concepts and emerging topics Int J Mol Sci 2021 22 13 6651 10.3390/ijms22136651 34206294 PMC8268587 Ponzetti M, Rucci N. Osteoblast differentiation and signaling: established concepts and emerging topics. Int J Mol Sci. 2021;22(13):6651. 34206294 10.3390/ijms22136651 PMC8268587

Porwal K Pal S Dev K China SP Kumar Y Singh C Guava fruit extract and its triterpene constituents have osteoanabolic effect: Stimulation of osteoblast differentiation by activation of mitochondrial respiration via the Wnt/β-catenin signaling J Nutr Biochem 2017 44 22 34 10.1016/j.jnutbio.2017.02.011 28343085 Porwal K, Pal S, Dev K, China SP, Kumar Y, Singh C, et al. Guava fruit extract and its triterpene constituents have osteoanabolic effect: Stimulation of osteoblast differentiation by activation of mitochondrial respiration via the Wnt/β-catenin signaling. J Nutr Biochem. 2017;44:22–34. 28343085 10.1016/j.jnutbio.2017.02.011

Prabhu KS The selenoprotein P-LRP5/6-WNT3A complex promotes tumorigenesis in sporadic colorectal cancer J Clin Invest 2023 133 13 e165988 10.1172/JCI171885 37395277 PMC10313358 Prabhu KS. The selenoprotein P-LRP5/6-WNT3A complex promotes tumorigenesis in sporadic colorectal cancer. J Clin Invest. 2023;133(13):e165988. 37395277 10.1172/JCI171885 PMC10313358

Punchihewa C Ferreira AM Cassell R Rodrigues P Fujii N Sequence requirement and subtype specificity in the high-affinity interaction between human frizzled and dishevelled proteins Protein Sci 2009 18 5 994 1002 10.1002/pro.109 19388021 PMC2771301 Punchihewa C, Ferreira AM, Cassell R, Rodrigues P, Fujii N. Sequence requirement and subtype specificity in the high-affinity interaction between human frizzled and dishevelled proteins. Protein Sci. 2009;18(5):994–1002. 19388021 10.1002/pro.109 PMC2771301

Qi X Hu Q Elghobashi-Meinhardt N Long T Chen H Li X Molecular basis of Wnt biogenesis, secretion, and Wnt7-specific signaling Cell 2023 186 23 5028 40.e14 10.1016/j.cell.2023.09.021 37852257 PMC10841698 Qi X, Hu Q, Elghobashi-Meinhardt N, Long T, Chen H, Li X. Molecular basis of Wnt biogenesis, secretion, and Wnt7-specific signaling. Cell. 2023;186(23):5028-40.e14. 37852257 10.1016/j.cell.2023.09.021 PMC10841698

Ren Z Zou W Cui J Liu L Qing Y Li Y Geraniin suppresses tumor cell growth and triggers apoptosis in human glioma via inhibition of STAT3 signaling Cytotechnology 2017 69 5 765 773 10.1007/s10616-017-0085-4 28374108 PMC5595748 Ren Z, Zou W, Cui J, Liu L, Qing Y, Li Y. Geraniin suppresses tumor cell growth and triggers apoptosis in human glioma via inhibition of STAT3 signaling. Cytotechnology. 2017;69(5):765–73. 28374108 10.1007/s10616-017-0085-4 PMC5595748

Riddle RC Diegel CR Leslie JM Van Koevering KK Faugere MC Clemens TL Lrp5 and Lrp6 exert overlapping functions in osteoblasts during postnatal bone acquisition PLoS ONE 2013 8 5 e63323 10.1371/journal.pone.0063323 23675479 PMC3651091 Riddle RC, Diegel CR, Leslie JM, Van Koevering KK, Faugere MC, Clemens TL, et al. Lrp5 and Lrp6 exert overlapping functions in osteoblasts during postnatal bone acquisition. PLoS ONE. 2013;8(5):e63323. 23675479 10.1371/journal.pone.0063323 PMC3651091

Routledge D Scholpp S Mechanisms of intercellular Wnt transport Development 2019 146 10 176073 10.1242/dev.176073 31092504 Routledge D, Scholpp S. Mechanisms of intercellular Wnt transport. Development. 2019;146(10):176073. 10.1242/dev.176073 31092504

Rybchyn MS Islam KS Brennan-Speranza TC Cheng Z Brennan SC Chang W Homer1 mediates CaSR-dependent activation of mTOR complex 2 and initiates a novel pathway for AKT-dependent β-catenin stabilization in osteoblasts J Biol Chem 2019 294 44 16337 16350 10.1074/jbc.RA118.006587 31527082 PMC6827303 Rybchyn MS, Islam KS, Brennan-Speranza TC, Cheng Z, Brennan SC, Chang W, et al. Homer1 mediates CaSR-dependent activation of mTOR complex 2 and initiates a novel pathway for AKT-dependent β-catenin stabilization in osteoblasts. J Biol Chem. 2019;294(44):16337–50. 31527082 10.1074/jbc.RA118.006587 PMC6827303

Sánchez-Cruz A Villarejo-Zori B Marchena M Zaldivar-Díez J Palomo V Gil C Modulation of GSK-3 provides cellular and functional neuroprotection in the rd10 mouse model of retinitis pigmentosa Mol Neurodegener 2018 13 1 19 10.1186/s13024-018-0251-y 29661219 PMC5902946 Sánchez-Cruz A, Villarejo-Zori B, Marchena M, Zaldivar-Díez J, Palomo V, Gil C, et al. Modulation of GSK-3 provides cellular and functional neuroprotection in the rd10 mouse model of retinitis pigmentosa. Mol Neurodegener. 2018;13(1):19. 29661219 10.1186/s13024-018-0251-y PMC5902946

Sebastian A Hum NR Murugesh DK Hatsell S Economides AN Loots GG Wnt co-receptors Lrp5 and Lrp6 differentially mediate Wnt3a signaling in osteoblasts PLoS ONE 2017 12 11 e0188264 10.1371/journal.pone.0188264 29176883 PMC5703471 Sebastian A, Hum NR, Murugesh DK, Hatsell S, Economides AN, Loots GG. Wnt co-receptors Lrp5 and Lrp6 differentially mediate Wnt3a signaling in osteoblasts. PLoS ONE. 2017;12(11):e0188264. 29176883 10.1371/journal.pone.0188264 PMC5703471

Singh S Mishra A Mohanbhai SJ Tiwari V Chaturvedi RK Khurana S Axin-2 knockdown promote mitochondrial biogenesis and dopaminergic neurogenesis by regulating Wnt/β-catenin signaling in rat model of Parkinson's disease Free Radic Biol Med 2018 129 73 87 10.1016/j.freeradbiomed.2018.08.033 30176346 Singh S, Mishra A, Mohanbhai SJ, Tiwari V, Chaturvedi RK, Khurana S, et al. Axin-2 knockdown promote mitochondrial biogenesis and dopaminergic neurogenesis by regulating Wnt/β-catenin signaling in rat model of Parkinson’s disease. Free Radic Biol Med. 2018;129:73–87. 30176346 10.1016/j.freeradbiomed.2018.08.033

Song GL Xiao M Wan XY Deng J Ling JD Tian YG MiR-130a-3p suppresses colorectal cancer growth by targeting Wnt Family Member 1 (WNT1) Bioengineered 2021 12 1 8407 8418 10.1080/21655979.2021.1977556 34657551 PMC8806712 Song GL, Xiao M, Wan XY, Deng J, Ling JD, Tian YG, et al. MiR-130a-3p suppresses colorectal cancer growth by targeting Wnt Family Member 1 (WNT1). Bioengineered. 2021;12(1):8407–18. 34657551 10.1080/21655979.2021.1977556 PMC8806712

Spit M Fenderico N Jordens I Radaszkiewicz T Lindeboom RG Bugter JM RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer Embo j 2020 39 18 e103932 10.15252/embj.2019103932 32965059 PMC7503102 Spit M, Fenderico N, Jordens I, Radaszkiewicz T, Lindeboom RG, Bugter JM, et al. RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer. Embo j. 2020;39(18):e103932. 32965059 10.15252/embj.2019103932 PMC7503102

Srivastava S Flora SJS Fluoride in Drinking Water and Skeletal Fluorosis: a Review of the Global Impact Curr Environ Health Rep 2020 7 2 140 146 10.1007/s40572-020-00270-9 32207100 Srivastava S, Flora SJS. Fluoride in Drinking Water and Skeletal Fluorosis: a Review of the Global Impact. Curr Environ Health Rep. 2020;7(2):140–6. 32207100 10.1007/s40572-020-00270-9

Stevenson PC Simmonds MS Yule MA Veitch NC Kite GC Irwin D Insect antifeedant furanocoumarins from Tetradium daniellii Phytochemistry 2003 63 1 41 46 10.1016/S0031-9422(02)00748-3 12657296 Stevenson PC, Simmonds MS, Yule MA, Veitch NC, Kite GC, Irwin D, et al. Insect antifeedant furanocoumarins from Tetradium daniellii. Phytochemistry. 2003;63(1):41–6. 12657296 10.1016/s0031-9422(02)00748-3

Suh KS Choi EM Lee YS Kim YS Protective effect of albiflorin against oxidative-stress-mediated toxicity in osteoblast-like MC3T3-E1 cells Fitoterapia 2013 89 33 41 10.1016/j.fitote.2013.05.016 23707745 Suh KS, Choi EM, Lee YS, Kim YS. Protective effect of albiflorin against oxidative-stress-mediated toxicity in osteoblast-like MC3T3-E1 cells. Fitoterapia. 2013;89:33–41. 23707745 10.1016/j.fitote.2013.05.016

Sun XL Chen ZH Guo X Wang J Ge M Wong SZH Stem cell competition driven by the Axin2-p53 axis controls brain size during murine development Dev Cell 2023 58 9 744 59.e11 10.1016/j.devcel.2023.03.016 37054704 Sun XL, Chen ZH, Guo X, Wang J, Ge M, Wong SZH, et al. Stem cell competition driven by the Axin2-p53 axis controls brain size during murine development. Dev Cell. 2023;58(9):744-59.e11. 37054704 10.1016/j.devcel.2023.03.016

Suthon S Perkins RS Lin J Crockarell JR Jr Miranda-Carboni GA Krum SA GATA4 and estrogen receptor alpha bind at SNPs rs9921222 and rs10794639 to regulate AXIN1 expression in osteoblasts Hum Genet 2022 141 12 1849 1861 10.1007/s00439-022-02463-8 35678873 Suthon S, Perkins RS, Lin J, Crockarell JR Jr, Miranda-Carboni GA, Krum SA. GATA4 and estrogen receptor alpha bind at SNPs rs9921222 and rs10794639 to regulate AXIN1 expression in osteoblasts. Hum Genet. 2022;141(12):1849–61. 35678873 10.1007/s00439-022-02463-8

Suzuki H Watkins DN Jair KW Schuebel KE Markowitz SD Chen WD Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer Nat Genet 2004 36 4 417 422 10.1038/ng1330 15034581 Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD, Chen WD, et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet. 2004;36(4):417–22. 15034581 10.1038/ng1330

Takahashi-Yanaga F Activator or inhibitor? GSK-3 as a new drug target Biochem Pharmacol 2013 86 2 191 199 10.1016/j.bcp.2013.04.022 23643839 Takahashi-Yanaga F. Activator or inhibitor? GSK-3 as a new drug target. Biochem Pharmacol. 2013;86(2):191–9. 23643839 10.1016/j.bcp.2013.04.022

Tauriello DV Jordens I Kirchner K Slootstra JW Kruitwagen T Bouwman BA Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled Proc Natl Acad Sci U S A 2012 109 14 E812 E820 10.1073/pnas.1114802109 22411803 PMC3325702 Tauriello DV, Jordens I, Kirchner K, Slootstra JW, Kruitwagen T, Bouwman BA, et al. Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled. Proc Natl Acad Sci U S A. 2012;109(14):E812–20. 22411803 10.1073/pnas.1114802109 PMC3325702

Tian R Tian J Zuo X Ren S Zhang H Liu H RACK1 facilitates breast cancer progression by competitively inhibiting the binding of β-catenin to PSMD2 and enhancing the stability of β-catenin Cell Death Dis 2023 14 10 685 10.1038/s41419-023-06191-3 37848434 PMC10582012 Tian R, Tian J, Zuo X, Ren S, Zhang H, Liu H, et al. RACK1 facilitates breast cancer progression by competitively inhibiting the binding of β-catenin to PSMD2 and enhancing the stability of β-catenin. Cell Death Dis. 2023;14(10):685. 37848434 10.1038/s41419-023-06191-3 PMC10582012

Tonk CH Shoushrah SH Babczyk P El Khaldi-Hansen B Schulze M Herten M Therapeutic treatments for osteoporosis-which combination of pills is the best among the bad? Int J Mol Sci 2022 23 3 1393 10.3390/ijms23031393 35163315 PMC8836178 Tonk CH, Shoushrah SH, Babczyk P, El Khaldi-Hansen B, Schulze M, Herten M, et al. Therapeutic treatments for osteoporosis-which combination of pills is the best among the bad? Int J Mol Sci. 2022;23(3):1393. 35163315 10.3390/ijms23031393 PMC8836178

Ugolkov A Gaisina I Zhang JS Billadeau DD White K Kozikowski A GSK-3 inhibition overcomes chemoresistance in human breast cancer Cancer Lett 2016 380 2 384 392 10.1016/j.canlet.2016.07.006 27424289 PMC5786372 Ugolkov A, Gaisina I, Zhang JS, Billadeau DD, White K, Kozikowski A, et al. GSK-3 inhibition overcomes chemoresistance in human breast cancer. Cancer Lett. 2016;380(2):384–92. 27424289 10.1016/j.canlet.2016.07.006 PMC5786372

Vlashi R Zhang X Wu M Chen G Wnt signaling: essential roles in osteoblast differentiation, bone metabolism and therapeutic implications for bone and skeletal disorders Genes Dis 2023 10 4 1291 1317 10.1016/j.gendis.2022.07.011 37397540 PMC10311035 Vlashi R, Zhang X, Wu M, Chen G. Wnt signaling: essential roles in osteoblast differentiation, bone metabolism and therapeutic implications for bone and skeletal disorders. Genes Dis. 2023;10(4):1291–317. 37397540 10.1016/j.gendis.2022.07.011 PMC10311035

Wang J Xia Y Li J Wang W miR-129-5p in exosomes inhibits diabetes-associated osteogenesis in the jaw via targeting FZD4 Biochem Biophys Res Commun 2021 566 87 93 10.1016/j.bbrc.2021.05.072 34119828 Wang J, Xia Y, Li J, Wang W. miR-129-5p in exosomes inhibits diabetes-associated osteogenesis in the jaw via targeting FZD4. Biochem Biophys Res Commun. 2021;566:87–93. 34119828 10.1016/j.bbrc.2021.05.072

Wang L Wang J Yin X Guan X Li Y Xin C GIPC2 interacts with Fzd7 to promote prostate cancer metastasis by activating WNT signaling Oncogene 2022 41 18 2609 2623 10.1038/s41388-022-02255-4 35347223 PMC9054671 Wang L, Wang J, Yin X, Guan X, Li Y, Xin C, et al. GIPC2 interacts with Fzd7 to promote prostate cancer metastasis by activating WNT signaling. Oncogene. 2022a;41(18):2609–23. 35347223 10.1038/s41388-022-02255-4 PMC9054671

Wang X Tian Y Liang X Yin C Huai Y Zhao Y Bergamottin promotes osteoblast differentiation and bone formation via activating the Wnt/β-catenin signaling pathway Food Funct 2022 13 5 2913 2924 10.1039/D1FO02755G 35188515 Wang X, Tian Y, Liang X, Yin C, Huai Y, Zhao Y, et al. Bergamottin promotes osteoblast differentiation and bone formation via activating the Wnt/β-catenin signaling pathway. Food Funct. 2022b;13(5):2913–24. 35188515 10.1039/d1fo02755g

Wang D Wu S He J Sun L Zhu H Zhang Y FAT4 overexpression promotes antitumor immunity by regulating the β-catenin/STT3/PD-L1 axis in cervical cancer J Exp Clin Cancer Res 2023 42 1 222 10.1186/s13046-023-02758-2 37658376 PMC10472690 Wang D, Wu S, He J, Sun L, Zhu H, Zhang Y, et al. FAT4 overexpression promotes antitumor immunity by regulating the β-catenin/STT3/PD-L1 axis in cervical cancer. J Exp Clin Cancer Res. 2023;42(1):222. 37658376 10.1186/s13046-023-02758-2 PMC10472690

Wang J Yang J Tang Z Yu Y Chen H Yu Q Curculigo orchioides polysaccharide COP70–1 stimulates osteogenic differentiation of MC3T3-E1 cells by activating the BMP and Wnt signaling pathways Int J Biol Macromol 2023 248 125879 10.1016/j.ijbiomac.2023.125879 37473884 Wang J, Yang J, Tang Z, Yu Y, Chen H, Yu Q, et al. Curculigo orchioides polysaccharide COP70–1 stimulates osteogenic differentiation of MC3T3-E1 cells by activating the BMP and Wnt signaling pathways. Int J Biol Macromol. 2023;248:125879. 37473884 10.1016/j.ijbiomac.2023.125879

Weivoda MM Ruan M Hachfeld CM Pederson L Howe A Davey RA Wnt signaling inhibits osteoclast differentiation by activating canonical and noncanonical cAMP/PKA pathways J Bone Miner Res 2016 31 1 65 75 10.1002/jbmr.2599 26189772 PMC4758681 Weivoda MM, Ruan M, Hachfeld CM, Pederson L, Howe A, Davey RA, et al. Wnt signaling inhibits osteoclast differentiation by activating canonical and noncanonical cAMP/PKA pathways. J Bone Miner Res. 2016;31(1):65–75. 26189772 10.1002/jbmr.2599 PMC4758681

Wiese KE Nusse R van Amerongen R Wnt signalling: conquering complexity Development 2018 145 12 dev165902 10.1242/dev.165902 29945986 Wiese KE, Nusse R, van Amerongen R. Wnt signalling: conquering complexity. Development. 2018;145(12):dev165902. 29945986 10.1242/dev.165902

Wo D Peng J Ren DN Qiu L Chen J Zhu Y Opposing roles of Wnt inhibitors IGFBP-4 and Dkk1 in cardiac ischemia by differential targeting of LRP5/6 and β-catenin Circulation 2016 134 24 1991 2007 10.1161/CIRCULATIONAHA.116.024441 27803037 Wo D, Peng J, Ren DN, Qiu L, Chen J, Zhu Y, et al. Opposing roles of Wnt inhibitors IGFBP-4 and Dkk1 in cardiac ischemia by differential targeting of LRP5/6 and β-catenin. Circulation. 2016;134(24):1991–2007. 27803037 10.1161/CIRCULATIONAHA.116.024441

Wu G Huang H Garcia Abreu J He X Inhibition of GSK3 phosphorylation of beta-catenin via phosphorylated PPPSPXS motifs of Wnt coreceptor LRP6 PLoS ONE 2009 4 3 e4926 10.1371/journal.pone.0004926 19293931 PMC2654145 Wu G, Huang H, Garcia Abreu J, He X. Inhibition of GSK3 phosphorylation of beta-catenin via phosphorylated PPPSPXS motifs of Wnt coreceptor LRP6. PLoS ONE. 2009;4(3):e4926. 19293931 10.1371/journal.pone.0004926 PMC2654145

Wu LH Li P Zhao QL Piao JL Jiao YF Kadowaki M Arbutin, an intracellular hydroxyl radical scavenger, protects radiation-induced apoptosis in human lymphoma U937 cells Apoptosis 2014 19 11 1654 1663 10.1007/s10495-014-1032-x 25187044 Wu LH, Li P, Zhao QL, Piao JL, Jiao YF, Kadowaki M, et al. Arbutin, an intracellular hydroxyl radical scavenger, protects radiation-induced apoptosis in human lymphoma U937 cells. Apoptosis. 2014;19(11):1654–63. 25187044 10.1007/s10495-014-1032-x

Wu L Wei Q Lv Y Xue J Zhang B Sun Q Wnt/β-catenin pathway is involved in cadmium-induced inhibition of osteoblast differentiation of bone marrow mesenchymal stem cells Int J Mol Sci 2019 20 6 1519 10.3390/ijms20061519 30917596 PMC6471709 Wu L, Wei Q, Lv Y, Xue J, Zhang B, Sun Q, et al. Wnt/β-catenin pathway is involved in cadmium-induced inhibition of osteoblast differentiation of bone marrow mesenchymal stem cells. Int J Mol Sci. 2019;20(6):1519. 30917596 10.3390/ijms20061519 PMC6471709

Wu Q Du X Cheng J Qi X Liu H Lv X PECAM-1 drives β-catenin-mediated EndMT via internalization in colon cancer with diabetes mellitus Cell Commun Signal 2023 21 1 203 10.1186/s12964-023-01193-2 37580771 PMC10426208 Wu Q, Du X, Cheng J, Qi X, Liu H, Lv X, et al. PECAM-1 drives β-catenin-mediated EndMT via internalization in colon cancer with diabetes mellitus. Cell Commun Signal. 2023;21(1):203. 37580771 10.1186/s12964-023-01193-2 PMC10426208

Xia B Xu B Sun Y Xiao L Pan J Jin H The effects of Liuwei Dihuang on canonical Wnt/β-catenin signaling pathway in osteoporosis J Ethnopharmacol 2014 153 1 133 141 10.1016/j.jep.2014.01.040 24530448 Xia B, Xu B, Sun Y, Xiao L, Pan J, Jin H, et al. The effects of Liuwei Dihuang on canonical Wnt/β-catenin signaling pathway in osteoporosis. J Ethnopharmacol. 2014;153(1):133–41. 24530448 10.1016/j.jep.2014.01.040

Xiang Y Zhang H Fan CQ Yue JM Novel diterpenoids and diterpenoid glycosides from Siegesbeckia orientalis J Nat Prod 2004 67 9 1517 1521 10.1021/np0400407 15387652 Xiang Y, Zhang H, Fan CQ, Yue JM. Novel diterpenoids and diterpenoid glycosides from Siegesbeckia orientalis. J Nat Prod. 2004;67(9):1517–21. 15387652 10.1021/np0400407

Xiao Y Xie X Chen Z Yin G Kong W Zhou J Advances in the roles of ATF4 in osteoporosis Biomed Pharmacother 2023 169 115864 10.1016/j.biopha.2023.115864 37948991 Xiao Y, Xie X, Chen Z, Yin G, Kong W, Zhou J. Advances in the roles of ATF4 in osteoporosis. Biomed Pharmacother. 2023;169:115864. 37948991 10.1016/j.biopha.2023.115864

Xu YJ Mei Y Shi XQ Zhang YF Wang XY Guan L Albiflorin ameliorates memory deficits in APP/PS1 transgenic mice via ameliorating mitochondrial dysfunction Brain Res 2019 1719 113 123 10.1016/j.brainres.2019.05.037 31150651 Xu YJ, Mei Y, Shi XQ, Zhang YF, Wang XY, Guan L, et al. Albiflorin ameliorates memory deficits in APP/PS1 transgenic mice via ameliorating mitochondrial dysfunction. Brain Res. 2019;1719:113–23. 31150651 10.1016/j.brainres.2019.05.037

Xu T Zeng Y Shi L Yang Q Chen Y Wu G Targeting NEK2 impairs oncogenesis and radioresistance via inhibiting the Wnt1/β-catenin signaling pathway in cervical cancer J Exp Clin Cancer Res 2020 39 1 183 10.1186/s13046-020-01659-y 32907622 PMC7488040 Xu T, Zeng Y, Shi L, Yang Q, Chen Y, Wu G, et al. Targeting NEK2 impairs oncogenesis and radioresistance via inhibiting the Wnt1/β-catenin signaling pathway in cervical cancer. J Exp Clin Cancer Res. 2020;39(1):183. 32907622 10.1186/s13046-020-01659-y PMC7488040

Xue W Yang L Chen C Ashrafizadeh M Tian Y Sun R Wnt/β-catenin-driven EMT regulation in human cancers Cell Mol Life Sci 2024 81 1 79 10.1007/s00018-023-05099-7 38334836 PMC10857981 Xue W, Yang L, Chen C, Ashrafizadeh M, Tian Y, Sun R. Wnt/β-catenin-driven EMT regulation in human cancers. Cell Mol Life Sci. 2024;81(1):79. 38334836 10.1007/s00018-023-05099-7 PMC10857981

Yao B Liu B Shi L Li X Ren C Cai M PAFR selectively mediates radioresistance and irradiation-induced autophagy suppression in prostate cancer cells Oncotarget 2017 8 8 13846 13854 10.18632/oncotarget.14647 28099922 PMC5355143 Yao B, Liu B, Shi L, Li X, Ren C, Cai M, et al. PAFR selectively mediates radioresistance and irradiation-induced autophagy suppression in prostate cancer cells. Oncotarget. 2017;8(8):13846–54. 28099922 10.18632/oncotarget.14647 PMC5355143

Yokota Y Kim WY Chen Y Wang X Stanco A Komuro Y The adenomatous polyposis coli protein is an essential regulator of radial glial polarity and construction of the cerebral cortex Neuron 2009 61 1 42 56 10.1016/j.neuron.2008.10.053 19146812 PMC2804250 Yokota Y, Kim WY, Chen Y, Wang X, Stanco A, Komuro Y, et al. The adenomatous polyposis coli protein is an essential regulator of radial glial polarity and construction of the cerebral cortex. Neuron. 2009;61(1):42–56. 19146812 10.1016/j.neuron.2008.10.053 PMC2804250

Yoshida Y Tanaka S Umemori H Minowa O Usui M Ikematsu N Negative regulation of BMP/Smad signaling by Tob in osteoblasts Cell 2000 103 7 1085 1097 10.1016/S0092-8674(00)00211-7 11163184 Yoshida Y, Tanaka S, Umemori H, Minowa O, Usui M, Ikematsu N, et al. Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell. 2000;103(7):1085–97. 11163184 10.1016/s0092-8674(00)00211-7

Yu F Liu Z Tong Z Zhao Z Liang H Soybean isoflavone treatment induces osteoblast differentiation and proliferation by regulating analysis of Wnt/β-catenin pathway Gene 2015 573 2 273 277 10.1016/j.gene.2015.07.054 26190158 Yu F, Liu Z, Tong Z, Zhao Z, Liang H. Soybean isoflavone treatment induces osteoblast differentiation and proliferation by regulating analysis of Wnt/β-catenin pathway. Gene. 2015;573(2):273–7. 26190158 10.1016/j.gene.2015.07.054

Yu S Yerges-Armstrong LM Chu Y Zmuda JM Zhang Y Transcriptional Regulation of Frizzled-1 in Human Osteoblasts by Sp1 PLoS ONE 2016 11 10 e0163277 10.1371/journal.pone.0163277 27695039 PMC5047477 Yu S, Yerges-Armstrong LM, Chu Y, Zmuda JM, Zhang Y. Transcriptional Regulation of Frizzled-1 in Human Osteoblasts by Sp1. PLoS ONE. 2016;11(10):e0163277. 27695039 10.1371/journal.pone.0163277 PMC5047477

Yu K Jiang Z Miao X Yu Z Du X Lai K circRNA422 enhanced osteogenic differentiation of bone marrow mesenchymal stem cells during early osseointegration through the SP7/LRP5 axis Mol Ther 2022 30 10 3226 3240 10.1016/j.ymthe.2022.05.020 35642253 PMC9552913 Yu K, Jiang Z, Miao X, Yu Z, Du X, Lai K, et al. circRNA422 enhanced osteogenic differentiation of bone marrow mesenchymal stem cells during early osseointegration through the SP7/LRP5 axis. Mol Ther. 2022;30(10):3226–40. 35642253 10.1016/j.ymthe.2022.05.020 PMC9552913

Yuan T Zhang J Zhao Y Guo Y Fan S Single-cell RNA sequencing of intestinal crypts reveals vital events in damage repair and the double-edged sword effect of the Wnt3/β-catenin pathway in irradiated mice Redox Biol 2023 68 102942 10.1016/j.redox.2023.102942 37918127 PMC10638071 Yuan T, Zhang J, Zhao Y, Guo Y, Fan S. Single-cell RNA sequencing of intestinal crypts reveals vital events in damage repair and the double-edged sword effect of the Wnt3/β-catenin pathway in irradiated mice. Redox Biol. 2023;68:102942. 37918127 10.1016/j.redox.2023.102942 PMC10638071

Zeng X Tamai K Doble B Li S Huang H Habas R A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation Nature 2005 438 7069 873 877 10.1038/nature04185 16341017 PMC2100418 Zeng X, Tamai K, Doble B, Li S, Huang H, Habas R, et al. A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature. 2005;438(7069):873–7. 16341017 10.1038/nature04185 PMC2100418

Zhang H Cao Y Chen L Wang J Tian Q Wang N A polysaccharide from Polygonatum sibiricum attenuates amyloid-β-induced neurotoxicity in PC12 cells Carbohydr Polym 2015 117 879 886 10.1016/j.carbpol.2014.10.034 25498712 Zhang H, Cao Y, Chen L, Wang J, Tian Q, Wang N, et al. A polysaccharide from Polygonatum sibiricum attenuates amyloid-β-induced neurotoxicity in PC12 cells. Carbohydr Polym. 2015;117:879–86. 25498712 10.1016/j.carbpol.2014.10.034

Zhang Y Xu J Ren Z Meng Y Liu W Lu L Nicotinamide promotes pancreatic differentiation through the dual inhibition of CK1 and ROCK kinases in human embryonic stem cells Stem Cell Res Ther 2021 12 1 362 10.1186/s13287-021-02426-2 34172095 PMC8235863 Zhang Y, Xu J, Ren Z, Meng Y, Liu W, Lu L, et al. Nicotinamide promotes pancreatic differentiation through the dual inhibition of CK1 and ROCK kinases in human embryonic stem cells. Stem Cell Res Ther. 2021;12(1):362. 34172095 10.1186/s13287-021-02426-2 PMC8235863

Zheng S Lin J Pang Z Zhang H Wang Y Ma L Aberrant Cholesterol Metabolism and Wnt/β-Catenin Signaling Coalesce via Frizzled5 in Supporting Cancer Growth Adv Sci (Weinh) 2022 9 28 e2200750 10.1002/advs.202200750 35975457 PMC9534957 Zheng S, Lin J, Pang Z, Zhang H, Wang Y, Ma L, et al. Aberrant Cholesterol Metabolism and Wnt/β-Catenin Signaling Coalesce via Frizzled5 in Supporting Cancer Growth. Adv Sci (Weinh). 2022;9(28):e2200750. 35975457 10.1002/advs.202200750 PMC9534957

Zhou F Li F Fang P Dai T Yang B van Dam H Ubiquitin-specific protease 4 antagonizes osteoblast differentiation through dishevelled J Bone Miner Res 2016 31 10 1888 1898 10.1002/jbmr.2863 27128386 Zhou F, Li F, Fang P, Dai T, Yang B, van Dam H, et al. Ubiquitin-specific protease 4 antagonizes osteoblast differentiation through dishevelled. J Bone Miner Res. 2016a;31(10):1888–98. 27128386 10.1002/jbmr.2863

Zhou J Ahmad F Parikh S Hoffman NE Rajan S Verma VK Loss of adult cardiac myocyte GSK-3 leads to mitotic catastrophe resulting in fatal dilated cardiomyopathy Circ Res 2016 118 8 1208 1222 10.1161/CIRCRESAHA.116.308544 26976650 PMC4843504 Zhou J, Ahmad F, Parikh S, Hoffman NE, Rajan S, Verma VK, et al. Loss of adult cardiac myocyte GSK-3 leads to mitotic catastrophe resulting in fatal dilated cardiomyopathy. Circ Res. 2016b;118(8):1208–22. 26976650 10.1161/CIRCRESAHA.116.308544 PMC4843504

Zhu B Xue F Zhang C Li G Ginkgolide B promotes osteoblast differentiation via activation of canonical Wnt signalling and alleviates osteoporosis through a bone anabolic way J Cell Mol Med 2019 23 8 5782 5793 10.1111/jcmm.14503 31225702 PMC6653448 Zhu B, Xue F, Zhang C, Li G. Ginkgolide B promotes osteoblast differentiation via activation of canonical Wnt signalling and alleviates osteoporosis through a bone anabolic way. J Cell Mol Med. 2019;23(8):5782–93. 31225702 10.1111/jcmm.14503 PMC6653448