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Proteoglycans as Molecular Regulators of Bone Metastasis: Extracellular Matrix Remodeling, Tumor-Bone Crosstalk, Dormancy, and Therapeutic Opportunities.

Background: Bone metastasis is a frequent and debilitating complication of advanced cancer, particularly in breast and prostate cancer, and is driven by complex interactions among tumor cells, bone-resident cells, immune populations, vascular components, and the extracellular matrix. Within this specialized microenvironment, proteoglycans have emerged as key molecular regulators of tumor-bone crosstalk, matrix remodeling, metastatic niche formation, dormancy, and therapeutic resistance. Methods: We conducted a narrative review using targeted searches of PubMed and Google Scholar for studies pu

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… Osteoblasts, osteoclasts, osteocytes, bone marrow stromal cells, endothelial cells, immune cells, and hematopoietic progenitors actively participate in the formation of the bone metastatic niche [ 11 , 12 ]. … To address this, functional models should incorporate tumor cells together with osteoblasts, osteoclasts, osteocytes, endothelial cells, macrophages, neutrophils, lymphocytes, and native or biomimetic extracellular matrix. …

The Role of Inflammatory Cytokines, the RANKL/OPG Axis, and the Immunoskeletal Interface in Physiological Bone Turnover and Osteoporosis.

Although it has long been recognized that inflammation, a consequence of immune-driven processes, significantly impacts bone turnover, the degree of centralization of skeletal and immune functions has begun to be dissected only recently. It is now recognized that formation of osteoclasts, the bone resorbing cells of the body, is centered on the key osteoclastogenic cytokine, receptor activator of NF- κ B ligand (RANKL). Although numerous inflammatory cytokines are now recognized to promote osteoclast formation and skeletal degradation, with just a few exceptions, RANKL is now considered to be

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… The importance of osteocytes as a source of RANKL was further confirmed using an osteocyte conditional RANKL KO model that revealed that the development of a significant osteopetrosis occurs in the absence of RANKL production by osteocytes [ 123 ] suggesting a critical role of osteocyte RANKL in basal … ROS have significant direct effects on the generation and survival of osteoclasts, osteoblasts, and osteocytes [ 284 ]. …

From undruggable to degradable: A deep learning-enabled framework for precision orthopaedic protein degradation.

BACKGROUND/OBJECTIVE: A fundamental translational impasse in musculoskeletal disorders-from osteoarthritis to bone metastases-is the "undruggability" of critical pathological drivers sequestered within anatomically restricted and avascular skeletal niches. While Targeted Protein Degradation (TPD) offers a revolutionary event-driven modality to eradicate these refractory targets, its clinical translation to orthopaedics is severely hindered by the physicochemical incompatibility of large degraders with dense extracellular matrices and the scarcity of bone-specific E3 ligases. METHODS: In this

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… (a) Kinetic Decoupling: The schematic graph illustrates the critical mismatch between the rapid decay of plasma pharmacokinetics (PK, blue line) and the sustained accumulation of protein degradation effects (orange dotted line) within long-lived skeletal cells (osteocytes/chondrocytes). … (a) Kinetic Decoupling: The schematic graph illustrates the critical mismatch between the rapid decay of plasma pharmacokinetics (PK, blue line) and the sustained accumulation of protein degradation effects (orange dotted line) within long-lived skeletal cells (osteocytes/chondrocytes). …

The Role of the Immune Response in the Development of Medication-Related Osteonecrosis of the Jaw.

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse drug effect. There are multiple hypotheses to explain the development of MRONJ. Reduced bone remodeling and infection or inflammation are considered central to the pathogenesis of MRONJ. In recent years, increasing evidence has shown that bisphosphonates (BPs)-mediated immunity dysfunction is associated with the pathophysiology of MRONJ. In a healthy state, mucosal immunity provides the first line of protection against pathogens and oral mucosal immune cells defense against potentially invading pathogens by media

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… Recently, it was demonstrated that osteocytes play an important role in inflammatory bone resorption mediated by inflammatory cytokines ( 108 ). … TNF-α directly enhances osteocyte rankl expression and promotes osteoclast formation. Front Immunol. (2019) 10:2925. 10.3389/fimmu.2019.02925 109. Kim H, Kim H, Choi Y, Bae M, Hwang D, Shin S, et al. Zoledronate enhances osteocyte-mediated osteoclast differentiation by IL-6/RANKL Axis. …

Bone-modifying therapy in multiple myeloma: a comprehensive review.

Multiple myeloma (MM) is a clonal hematologic malignancy characterized by plasma cell proliferation in the bone marrow. One of the most common clinical presentations is skeletal-related events (SREs), characterized by osteolysis of the bone, leading to a significant morbidity and mortality. The main aim of this review article is to provide an overview of the pathogenesis and evidence-based, guideline-recommended treatment of SREs. MM bone homeostasis is altered by numerous pathways and cytokines, leading to the pathogenesis of bone and osteolytic lesions. Historically, bisphosphonates were the

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… Although reduced in the bone of MM patients, osteocytes induce the activity of osteoclasts via the Notch 3 and 4 pathways and receptors, and active RANKL and OPG, leading to bone resorption and loss ( 26 ). … In vivo murine models show osteocyte apoptosis, changing the microenvironment and promoting homing and replication of the MM clone ( 58 ). This process is naturally inhibited by BPs ( 59 ). …

Unexpected and Deadly: Three Cases of Bone Marrow Necrosis.

Bone marrow necrosis (BMN) is a rare pathological diagnosis, with an incidence of 0.3% to 2%. It is most often associated with hematological malignancies and less commonly due to solid tumors, infections, medications, sickle cell disease, chemotherapy, radiotherapy, or idiopathic causes. We reviewed bone marrow biopsies performed in our institution from 2009 to 2019 and found three cases of BMN. Two cases were secondary to neoplastic causes, while the third one was possibly from alcohol abuse.

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… Figure 1 Hemotoxylin- and eosin-stained section of the bone marrow core biopsy showing necrosis of the bone, osteocytes (arrow), and the adjacent marrow with essentially absent hematopoietic elements (asterisk). 100x magnification. … Figure 2 There is viable bone trabecula with dark osteocyte nuclei visible (arrows). The cells surrounding the trabecula are necrotic (asterisks). 100x magnification. Hemotoxylin- and eosin-stained section. …

Female sex is associated with a lower risk of bone metastases and favourable prognosis in non-sex-specific cancers.

BackgroundThe objectives were to investigate the disparity in the prevalence of bone metastases (BM) between the sexes and to assess the effect of female sex on the development and prognosis of BM.MethodsCases of invasive non-sex-specific cancers diagnosed between 2010 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) program were used. The prevalence of BM was calculated by combining the prevalence of BM among different cancers. Multivariable logistic regression and proportion hazard regression were conducted to investigate the effect of female sex, and the results were poole

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… Androgen prevents hypogonadal bone loss via inhibition of resorption mediated by mature osteoblasts/osteocytes. Bone. 2012;51(5):835–846. doi: 10.1016/j.bone.2012.08.111. 25. Sinnesael M, Claessens F, Laurent M, Dubois V, Boonen S, Deboel L, et al. … Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: evidence from targeted AR disruption in mouse osteocytes. J Bone Miner Res. 2012;27(12):2535–2543. doi: 10.1002/jbmr.1713. 26. …

R-spondin signaling as a pivotal regulator of tissue development and homeostasis.

R-spondins (Rspos) are cysteine-rich secreted glycoproteins which control a variety of cellular functions and are essential for embryonic development and tissue homeostasis. R-spondins (Rspo1 to 4) have high structural similarity and share 60% sequence homology. It has been shown that their cysteine-rich furin-like (FU) domain and the thrombospondin (TSP) type I repeat domain are essential for initiating downstream signaling cascades and therefore for their biological functions. Although numerous studies have unveiled their pivotal role as critical developmental regulators, the most important

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… Osteoclasts differentiation is critically regulated by receptor activator of NF-κB ligand (RANKL) and its decoy receptor osteoprotegerin (OPG), which are secreted by osteoblasts [1] , [2] , [3] and probably also by osteocytes [4] , [5] . … Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med. 2011;17(10):1231–1234. doi: 10.1038/nm.2452. 5. Zhao S., Zhang Y.K., Harris S., Ahuja S.S., Bonewald L.F. MLO-Y4 osteocyte-like cells support osteoclast formation and activation. …

Предотвращение событий, связанных со скелетом, в новой диагностированной миеломе.

Несмотря на увеличение числа новых методов лечения недавно диагностированной множественной миеломы (НДММ), предотвращение событий, связанных со скелетом (СРП), по-прежнему является сложной задачей. В настоящем обзоре резюмируются механистические причины болезни костей миэломы, данные, подтверждающие использование бисфофонатов и ингибиторов РАНКЛ, а также оптимальное управление предотвращением НОС у пациентов НДММ. Как золедронная кислота (ZA), так и деносумаб являются приемлемыми вариантами обработки с сопоставимыми характеристиками безопасности и эффективности. Однако у пациентов, которые явл

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… Activation of Notch signaling in osteocytes by myeloma cells induces osteocyte apoptosis, stimulates RANKL expression, and increases Notch receptor expression in myeloma cells, stimulating their growth [ 16 ]. These mechanisms are depicted in Figure 1 . … Regular weight-bearing physical activity improves bone health through activation of osteocyte signaling and anabolic effects on bone mineral content and bone mineral density [ 54 ]. …

The Osteoclast in Bone Metastasis: Player and Target.

Bone metastases are frequently the final fate of breast and prostate cancer patients. According to the definition of metastasis as an incurable disease, to date there are no effective treatments for tumor-associated bone metastases and this represents a real challenge for the researchers in the field. The bone is a heterogeneous environment that represents a fertile soil for tumor cells, supporting their growth. Among the different cell types present in the bone, in this review we will focus our attention on the osteoclasts, which are crucial players in the so called “vicious cycle”, a phenome

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… Bone Remodeling: The Virtuous Cycle Bone cells, that is osteocytes, osteoblasts and osteoclasts, actively participate in the cycle of bone remodeling, following space and time well-controlled steps, as described: Activation phase. … Osteocytes, the bone cells buried in the bone matrix, having mechano-sensorial functions, can promote the activation phase following the perception of changes in mechanical loading. …

RANKL Drives Bone Metastasis in Mammary Cancer: Protective Effects of Anti-Resorptive Treatments.

Receptor activator of nuclear factor-κB ligand (RANKL) is essential for osteoclast formation and bone resorption, in osteolytic conditions such as osteoporosis and bone metastases. However, its role in metastasis progression remains incompletely understood. Herein, we examined whether the overexpression of human RANKL in transgenic mice (TgRANKL) affects their susceptibility to breast cancer bone metastasis compared to their wild-type (WT) littermates. Bone metastasis was induced by injecting EO771 mouse mammary adenocarcinoma cells into the caudal artery of syngeneic WT and TgRANKL mice. RANK

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… RANKL (receptor activator of nuclear factor-κB ligand), primarily produced by osteoblasts and osteocytes, is essential for the formation, activity, and survival of osteoclasts, the bone-resorbing cells [ 5 , 6 ]. … Evidence for Osteocyte Regulation of Bone Homeostasis through RANKL Expression Nat. Med. 2011 17 1231 1234 10.1038/nm.2452 21909105 7. Boyce B.F. Xing L. Functions of RANKL/RANK/OPG in Bone Modeling and Remodeling Arch. Biochem. …

Sclerostin Alters Tumor Cell Characteristics of Oral Squamous Cell Carcinoma and May Be a Key Player in Local Bone Invasion.

Localized jawbone invasion is a milestone in the progression of oral squamous cell carcinoma (OSCC). The factors that promote this process are not well understood. Sclerostin is known to be involved in bone metabolism and there are preliminary reports of its involvement in bone tumors and bone metastasis. To identify a possible involvement of sclerostin in the bone invasion process of OSCC, sclerostin expression was analyzed in vitro in two different human OSCC tumor cell lines by quantitative real-time polymerase chain reaction (qRT-PCR), and the effect of recombinant human (rh)-sclerostin tr

Histopathological findings affect quantitative values of single photon emission computed tomography in patients with antiresorptive agent-related osteonecrosis of the jaws.

OBJECTIVES: This study investigated the relationships between quantitative values calculated from bone single photon emission computed tomography/computed tomography (SPECT/CT) images and histopathological findings observed in surgical specimens from patients with antiresorptive agent-related osteonecrosis of the jaw (ARONJ); it sought to clarify histopathological factors that cause accumulation in bone SPECT/CT images of patients with ARONJ. METHODS: This study included 81 pathological specimens of 21 lesions obtained from 18 patients with ARONJ who underwent SPECT/CT and jaw resection. The

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… One oral and maxillofacial surgeon and one oral pathologist evaluated each specimen on the basis of the following factors: sequestration, defined as the presence or absence of osteocytes in bone lacunae (grade 0 or 1); degree of tissue fibrosis in the bone marrow space (grade 0–2); degree of trabecular … Top image indicates grade 1 sequestration: osteocytes are present in bone lacunae (arrowhead). Bottom image indicates grade 2: osteocytes are not present in bone lacunae (arrowhead). B. Assessment of tissue fibrosis in the bone marrow space (Azan stain, ×200). …

Bisphosphonate-related osteonecrosis. Application of adipose-derived stem cells in an experimental murine model.

BACKGROUND: Bisphosphonate-related osteonecrosis of the jaw is a pathological condition without effective established treatment and preventive strategies. The aim of this study was to analyse the effect of adipose-derived stem cells (ASC) in an experimental murine model of osteonecrosis. MATERIAL AND METHODS: 38 Wistar rats were injected intraperitoneally with zoledronic acid. After treatment, upper jaw molars were extracted. The animals were randomly assigned to one of two groups. In the control group, saline solution was applied over the alveolar sockets after the tooth extractions. In the

A Systematic Review of the Effects of Bisphosphonates on Osteoblasts In Vitro.

Bisphosphonates (BPs) are widely used to treat bone disorders, prevent skeletal-related events, and manage bone metastasis. These drugs are synthetic analogs of pyrophosphate and primarily function by inhibiting osteoclast activity. However, increasing evidence suggests that they also have an effect on osteoblasts. This systematic review aims to evaluate how bisphosphonates affect osteoblasts by summarizing findings from in vitro studies on the impact of BPs on osteoblast lineage cells, addressing the following question: "Do bisphosphonates affect osteoblast cell lineage function?". For this p

Calcium Phosphate Ceramics Can Prevent Bisphosphonate-Related Osteonecrosis of the Jaw.

Bisphosphonate-associated osteonecrosis of the jaw (BRONJ), a post-surgical non-healing wound condition, is one of the most common side effects in patients treated with nitrogen-containing bisphosphonates. Its physiopathology has been related with suppression of bone turnover, of soft tissue healing and infection. Biphasic calcium phosphates (BCP) are used as a drug delivery vehicle and as a bone substitute in surgical wounds. Due to their capacity to adsorb zoledronate, it was hypothesized these compounds might have a protective effect on the soft tissues in BRONJ wounds. To address this hypo

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… In the most apical region of the defect, there are areas of necrotic bone tissue characterized by the absence of osteocytes within their lacunae. However, in some cases, the direct apposition of immature bone tissue on these necrotic bone trabeculae can be visible. … In the newly formed trabecular bone is possible to observe besides the osteoblastic layer, a large density of osteocytes arranged irregularly, a typical aspect of immature bone tissue ( Figure 5 C). …

Hypophosphatemic rickets: diagnosis and treatment.

Hypophosphatemicrickets (HR) represents a heterogeneous group of disorders characterized by renal phosphate wasting, impaired bone mineralization, and skeletal deformities. This narrative review provides an overview of phosphate homeostasis and the molecular mechanisms underlying HR, focusing on the role of Fibroblast Growth Factor 23 (FGF23) in regulating renal phosphate use and vitamin D metabolism. The clinical, biochemical, and genetic features of both FGF23-dependent and -independent forms of HR are discussed, including X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic

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… Osteocytes and osteoblasts secrete FGF23, which circulates to the kidney and growth plates of growing children. … The PHEX protein is a membrane-associated metalloprotease expressed in osteocytes and odontoblasts. …

Mesenchymal stem cells in the treatment of osteonecrosis of the jaw.

Medication-related osteonecrosis of the jaw (MRONJ) has recently associated to the increase in antiresorptive and anti-angiogenic drugs prescriptions in the treatment of oncologic and osteoporotic patients. The physiopathogenesis of MRONJ remains unclear and available treatments are unsatisfactory. Newer pharmacological treatments have shown good results, but are not curative and could have major side effects. At the same time as pharmacological treatments, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic modality for tissue regeneration and repair. MSCs are multi-potentia

Comparison of the prophylactic use of ibandronate and its use in early-stage osteonecrosis in rats with steroid-induced osteonecrosis of the femoral head.

OBJECTIVES: The aim of this study was to investigate the effects of ibandronate before and after the onset of osteonecrosis in rats with steroid-induced osteonecrosis of the femoral head. MATERIALS AND METHODS: A total of 24 female Sprague-Dawley rats were used in this study. Three groups were formed with eight rats in each group. The first group was the prophylactic group that received ibandronate treatment before and after the onset of osteonecrosis (Group PT). The second group received ibandronate treatment three weeks after the development of osteonecrosis (Group TAO). The third group was

Refractory healing after surgical therapy of osteonecrosis of the jaw: associated risk factors in aged patients.

Purpose: Osteonecrosis of the jaw (ONJ), both medication-related and non medication-related, mainly occurs in aged patients. It needs surgical intervention. Refractory healing after an operation of ONJ can significantly lower the quality of life of elderly patients. The purpose of this study was to determine risk factors associated with refractory healing in aged patients. Patients and methods: We performed a retrospective study of ONJ in aged patients who underwent surgical treatments in a single institute during a 12-year period. Multiple logistic regression analysis was used to determine in

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… are altered, and increased insulin levels can also affect bone and elevate levels of advanced glycation end products causing complex alterations of vitamin D-related bone regulation. 24 , 25 Also, high blood glucose level can inhibit osteoclast differentiation and function and induce osteoblast and osteocyte … Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone . J Clin Invest . 1998 ; 102 ( 2 ): 274 – 282 . doi: 10.1172/JCI2799 9664068 PMC508885 32. …