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The Metabolic Features of Osteoblasts: Implications for Multiple Myeloma (MM) Bone Disease.

The study of osteoblast (OB) metabolism has recently received increased attention due to the considerable amount of energy used during the bone remodeling process. In addition to glucose, the main nutrient for the osteoblast lineages, recent data highlight the importance of amino acid and fatty acid metabolism in providing the fuel necessary for the proper functioning of OBs. Among the amino acids, it has been reported that OBs are largely dependent on glutamine (Gln) for their differentiation and activity. In this review, we describe the main metabolic pathways governing OBs' fate and functio

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… Osteocytes are the cells that probably determine which bone surface will be resorbed by OCs. They are interconnected in the bone matrix through a network of osteocyte canaliculi-containing osteocyte dendritic processes [ 39 ]. … Osteocytes as dynamic multifunctional cells. Ann. NY Acad. Sci. 2007;1116:281–290. doi: 10.1196/annals.1402.018. 40. Qin L., Liu W., Cao H., Xiao G. Molecular mechanosensors in osteocytes. Bone Res. 2020;8:23. doi: 10.1038/s41413-020-0099-y. 41. Sims N.A., Martin T.J. …

Current concepts in bone metastasis, contemporary therapeutic strategies and ongoing clinical trials.

BackgroundElucidation of mechanisms regulating bone metastasis has progressed significantly in recent years and this has translated to many new therapeutic options for patients with bone metastatic cancers. However, the rapid rate of progress in both the basic science literature and therapies undergoing clinical trials makes staying abreast with current developments challenging. This review seeks to provide an update on the current state of the science in bone metastasis research and give a snap shot of therapies in clinical trials for bone metastatic cancer.Main bodyBone metastasis represents

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… Even though osteocytes are surrounded by the bone matrix, they communicate through an extensive lacunar-cannicular network which connects the osteocytes to other osteocytes, the bone surface, and marrow cells. … IL-11 has been shown to be released from apoptotic osteocytes causing osteoclast differentiation [ 50 ]. Additionally, physical interactions and secreted factors from cancer cells such as multiple myeloma cells impact osteocyte function [ 51 ]. …

Advances in the research on myokine-driven regulation of bone metabolism.

The traditional view posits that bones and muscles interact primarily through mechanical coupling. However, recent studies have revealed that myokines, proteins secreted by skeletal muscle cells, play a crucial role in the regulation of bone metabolism. Myokines are widely involved in bone metabolism, influencing bone resorption and formation by interacting with factors related to bone cell secretion or influencing bone metabolic pathways. Here, we review the research progress on the myokine regulation of bone metabolism, discuss the mechanism of myokine regulation of bone metabolism, explore

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… Osteokines and muscle metabolism In 2006, osteocytes were proposed to be endocrine cells. FGF-23 expression was found to be significantly elevated in osteocytes of patients with hypophosphatemic rickets, targeting the kidney to regulate phosphate homeostasis [ 97 ]. … Since then, an increasing number of studies have shown that osteocytes produce a variety of cytokines such as osteocalcin, OPG, DKK1, stromal extracellular phosphoglycoprotein (MEPE), and PGE2. …

Myeloma Bone Disease: A Comprehensive Review.

Multiple myeloma (MM) is a neoplastic clonal proliferation of plasma cells in the bone marrow microenvironment, characterized by overproduction of heavy- and light-chain monoclonal proteins (M-protein). These proteins are mainly found in the serum and/or urine. Reduction in normal gammaglobulins (immunoparesis) leads to an increased risk of infection. The primary site of origin is the bone marrow for nearly all patients affected by MM with disseminated marrow involvement in most cases. MM is known to involve bones and result in myeloma bone disease. Osteolytic lesions are seen in 80% of patien

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… In adult bone, osteocytes comprise 90–95% of cells, whereas osteoclast and osteoblastic cells account for fewer than 10% of them [ 11 ]. Osteocytes function as the main regulators of bone homeostasis between osteoclast and osteoblasts [ 3 ]. … Osteocytes secrete cytokines including sclerostin, DKK1/Wnt pathway inhibitor, RANKL, and OPG. These osteocytes contribute to the activation of bone remodeling process. They respond to mechanical stimulation and initiate bone resorption. …

Association of Wnt Inhibitors, Bone Mineral Density and Lifestyle Parameters in Women with Breast Cancer Treated with Anastrozole Therapy.

AimTo determine the levels of Wnt inhibitors in patients treated with aromatase inhibitors (AIs) prior to therapy and to investigate their association with bone mineral density (BMD) and lifestyle parameters.Methods137 breast cancer patients were divided into a group treated with 1 mg of anastrozole and a group w/o anastrozole therapy. Serum concentrations of sclerostin and dickkopf1 (DKK1) were measured by ELISA. BMD was measured by dual-energy X-ray absorptiometry (DXA). Lifestyle factors were investigated by a self-reported questionnaire.ResultsSclerostin was significantly higher in the AI-

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… Increasing osteocytic expression of receptor activator of nuclear factor kappa B ligand (RANKL) consequently increases osteoclast production [ 12 ]. … While sclerostin is almost exclusively expressed in osteocytes [ 13 ], DKK1 is secreted by a variety of different cells and tissues including cancer cells. …

Editorial: Cancer and Bone Metastasis.

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Prevention of tooth extraction-triggered bisphosphonate-related osteonecrosis of the jaws with basic fibroblast growth factor: An experimental study in rats.

Osteonecrosis of the jaw induced by administration of bisphosphonates (BPs), BP-related osteonecrosis (BRONJ), typically develops after tooth extraction and is medically challenging. As BPs inhibit oral mucosal cell growth, we hypothesized that suppression of the wound healing-inhibiting effects could prevent BRONJ onset after tooth extraction. Since basic fibroblast growth factor (bFGF) promotes wound healing, but has a short half-life, we examined whether the initiation of BRONJ could be prevented by applying a bFGF-containing gelatin hydrogel over the extraction sockets of BRONJ model rats.

Inflammaging in periodontal, periapical, and malignancy-associated disease: drivers of alveolar bone loss and repair.

BACKGROUND: Aging significantly impacts bone metabolism through altered osteoblast/osteoclast dynamics, reduced stem cell regeneration, and chronic inflammaging. This narrative review explores how these age-related changes influence alveolar bone loss and regeneration in the oral cavity. METHODS: The review investigates key mechanisms-including immunosenescence and inflammasome activation-across three specific pathological contexts: (1) periodontitis, (2) periapical bone resorption, and (3) malignancy-associated osteolysis. Preclinical and clinical evidence were integrated to analyze the bone

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… In aged murine alveolar bone, osteocytes have been shown to upregulate SASP factors, including IL-6, IL-17, and matrix metalloproteinase-13 [ 21 ]. … Senolytic drugs, such as dasatinib and quercetin, have shown promise in improving bone density in aged mice by removing senescent osteocytes [ 50 ]. …

Ирисин предотвращает повреждение трабекулярных костей и проникновение опухоли в мышиную модель множественной миэломы.

Болезни костей, связанные с множественной миеломой (ММ), характеризуются остеолитическими повреждениями и патологическими переломами, которые по-прежнему являются приоритетной терапевтической задачей, несмотря на новые лекарственные средства, способствующие выживанию пациентов с MM. Антирезорптивные молекулы представляют собой главный вариант лечения костного заболевания, связанного с MM (MMBD), в то время как остеоанаболические молекулы в настоящее время изучаются. Среди последних мы здесь сосредоточили внимание на миокиновом ирисине, который способен увеличить массу костей в здоровых мышах,

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… These results are in agreement with Delgado-Calle et al., 32 who reported that in mice, osteocytes interacting with MM cells, express higher RankL levels than those of control mice. … Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma . Bloo d . 2017 ; 129 ( 26 ): 3452 – 3464 . 10.1182/blood-2017-03-773341 28515094 PMC5492093 …

Моделирование и нацеливание враждебной физико-химической ниши в метастазе костей: от экспериментальных платформ до нишевой терапии.

Метастаз рака до костей формируется не только из-за перекрестка опухолей, но и из-за враждебной физико-химической ниши, которая способствует стойкости к болезням и терапевтической недостаточности. Гипоксия, кислотность, минерализированная матричная архитектура, изменённая механика, интерстициальное давление, дисфункция перфузии и ограниченный перенос наркотиков влияют на метастатическое семя, общность, реактивацию, реконструкцию, боль и реакцию на лечение. Обычные two- размерные культуры и многие упрощенные three- размерные системы воспроизводят только отдельные особенности этой среды, часто п

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… Osteocyte incorporation Osteocytes should be incorporated when the model aims to capture mechanosensing, load-dependent signaling, or remodeling regulation, because they are the major mechanosensitive cells embedded within mineralized bone ( Dabaliz et al., 2026 ). … Osteocyte–tumor crosstalk can also directly modify metastatic behavior. …

Modeling osteoporosis to design and optimize pharmacological therapies comprising multiple drug types.

For the treatment of postmenopausal osteoporosis, several drug classes with different mechanisms of action are available. Since only a limited set of dosing regimens and drug combinations can be tested in clinical trials, it is currently unclear whether common medication strategies achieve optimal bone mineral density gains or are outperformed by alternative dosing schemes and combination therapies that have not been explored so far. Here, we develop a mathematical framework of drug interventions for postmenopausal osteoporosis that unifies fundamental mechanisms of bone remodeling and the mec

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… Osteocytes secrete sclerostin, a Wnt inhibitor interfering with extracellular binding of Wnt ligands ( Li et al., 2005 ). … Equation 11 : Sclerostin downregulates osteoblast to osteocyte conversion ( Atkins et al., 2011 ). …

Systemic administration of quality- and quantity-controlled PBMNCs reduces bisphosphonate-related osteonecrosis of jaw-like lesions in mice.

BACKGROUND: Definitive treatment strategies for bisphosphonate-related osteonecrosis of the jaw (BRONJ) have not been developed. Cell-based therapy is an attractive treatment method for intractable diseases in the medical and dental fields; however, approval has been challenging in dentistry. Recently, we developed quality- and quantity (QQ)-controlled peripheral blood mononuclear cells (PBMNCs) that have anti-inflammatory and pro-angiogenesis effects. The aim of this study was to investigate the effects of QQ-controlled PBMNC transplantation on BRONJ-like lesions in mice. METHODS: To create

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… The following parameters were histomorphometrically assessed to validate impaired tooth extraction socket healing showing human-like BRONJ conditions, as previously described [ 22 , 23 ]: N.Oc/BS (#/mm); osteocyte number in tooth extraction sockets [osteocyte density (#/mm 2 )]; empty osteocyte lacuna … number in tooth extraction sockets [empty lacunae (#/mm 2 )]; living bone area, designated as bone with normal osteocytes except for empty and pyknotic osteocyte lacunae [living bone (%)]; necrotic bone in extraction sockets, defined as the portion of bone in which there were greater than or equal to …

Epigenetic Regulation of Autophagy in Bone Metabolism.

The skeletal system is crucial for supporting bodily functions, protecting vital organs, facilitating hematopoiesis, and storing essential minerals. Skeletal homeostasis, which includes aspects such as bone density, structural integrity, and regenerative processes, is essential for normal skeletal function. Autophagy, an intricate intracellular mechanism for degrading and recycling cellular components, plays a multifaceted role in bone metabolism. It involves sequestering cellular waste, damaged proteins, and organelles within autophagosomes, which are then degraded and recycled. Autophagy's i

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… Autophagy can also enable the long-term terminal differentiation of osteocytes. … RANKL induces autophagy activation through pathways such as MAPK and NF-κB during this process. 158 Autophagy in Osteocytes Osteocytes establish an extensive interconnected network throughout the entire skeleton. …

Mechanical unloading aggravates bone destruction and tumor expansion in myeloma.

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… Osteocytes are embedded in the bone matrix, and major sensors of mechanical stress to regulate bone remodeling through interaction with bone marrow cells by their dendritic processes. 4 Osteocytes produce critical molecules for bone metabolism, including receptor activator of nuclear factor-κB ligand … After flushing out bone cavities to remove bone marrow cells, femurs were used for gene analysis in osteocytes embedded in bone. …

Evaluation of Local and Systemic Melatonin Administration on Bone Healing After Tooth Extraction in Bisphosphonate-Treated Rats.

BACKGROUND: The purpose of our study was to investigate the effects of systemic and local application of melatonin after tooth extraction in bisphosphonate applied rats, on the healing of extraction socket histopathologically and immunohistochemically. METHODS: Forty four Wistar albino rats were included in the study. Subjects were divided into 4 groups: Control (C), Bisphosphonate (BIF), Bisphosphonate + Local Melatonin (BIF + LM) and Bisphosphonate + Systemic Melatonin (BIF + SM). Zoledronic acid was applied intraperitoneally once a week from the beginning of the experiment to all the groups

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… In the BIF + LM and BIF + SM groups, necrotic areas and the density of empty lacunae were reduced, while viable osteocytes with distinct basophilic nuclei were frequently observed within the bone trabeculae. … Osteonecrosis is a term that is commonly used to describe the death of bone cells such as bone marrow stromal cells, preosteoblasts, mature osteoblasts, osteocytes, and osteoclasts [ 26 ]. …

Molecular mechanisms and clinical management of cancer bone metastasis.

As one of the most common metastatic sites of malignancies, bone has a unique microenvironment that allows metastatic tumor cells to grow and flourish. The fenestrated capillaries in the bone, bone matrix, and bone cells, including osteoblasts and osteoclasts, together maintain the homeostasis of the bone microenvironment. In contrast, tumor-derived factors act on bone components, leading to subsequent bone resorption or excessive bone formation. The various pathways involved also provide multiple targets for therapeutic strategies against bone metastases. In this review, we summarize the curr

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… Osteocyte regulation of bone mineral: a little give and take. Osteoporos. Int. 2012;23:2067–2079. doi: 10.1007/s00198-012-1915-z. 26. Bonewald LF. The amazing osteocyte. J. Bone Miner. Res. 2011;26:229–238. doi: 10.1002/jbmr.320. 27. Winkler DG, et al. … Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat. Genet. 2006;38:1310–1315. doi: 10.1038/ng1905. 31. Kramer I, et al. Osteocyte Wnt/beta-catenin signaling is required for normal bone homeostasis. Mol. Cell. …

Osteoclast Activation and Inflammatory Bone Diseases: Focusing on Receptors in Osteoclasts.

Bone homeostasis depends on the balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. An increasing number of studies have revealed that under inflammatory conditions, osteoclast overactivation is responsible for bone loss in relevant bone diseases. Multiple signaling pathways such as receptor activator of nuclear factor-kappa B ligand (RANKL) signaling are involved in osteoclast activation. These signaling pathways rely on various receptors expressed on the surface of osteoclast progenitor cells (OPCs) or osteoclasts, which are activated by their correspo

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… RANKL is expressed by multiple cells, of which osteocytes are considered an important source. … Fujiwara et al showed that knockout of RANKL in osteocytes inhibited osteoclast generation and bone loss in mouse bone tissue, suggesting the importance of osteocyte-derived RANKL. 44 As discussed previously, after binding to RANKL, RANK recruits TRAF6, which further activates NF-κB, MAPKs, tyrosine …

RANKL/RANK System-Based Mechanism for Breast Cancer Bone Metastasis and Related Therapeutic Strategies.

Breast cancer remains one of the most life-threatening tumors affecting women. Most patients with advanced breast cancer eventually develop metastatic diseases, which cause significant morbidity and mortality. Approximately two-thirds of patients with advanced breast cancer exhibit osteolytic-type bone metastasis, which seriously reduce the quality of life. Therefore, development of novel therapeutic strategies for treating breast cancer patients with bone metastasis is urgently required. The "seed and soil" theory, which describes the interaction between the circulating breast cancer cells (s

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… After the synthesis of the new bone matrix, osteoblasts either undergo apoptosis or are embedded in the bone matrix as osteocytes. Evidence showed that the survival of osteocytes is regulated by the osteoprotective factor semaphorin 3A (Sema3A). … Estrogen can induce osteocytes to express Sema3A, which acts on the receptors on osteocytes and activates GC-cGMP signaling to promote their survival ( Hayashi et al., 2019 ). …

Hematological Diseases and Osteoporosis.

Secondary osteoporosis is a common clinical problem faced by bone specialists, with a higher frequency in men than in women. One of several causes of secondary osteoporosis is hematological disease. There are numerous hematological diseases that can have a deleterious impact on bone health. In the literature, there is an abundance of evidence of bone involvement in patients affected by multiple myeloma, systemic mastocytosis, thalassemia, and hemophilia; some skeletal disorders are also reported in sickle cell disease. Recently, monoclonal gammopathy of undetermined significance appears to inc

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… Osteocytes act as orchestrators producing factors, such as RANKL and sclerostin, that influence osteoclast and osteoblast activities [ 2 ]. … In addition, bortezomib partially inhibits osteocyte autophagy and apoptosis induced by MM and consequently increases the number of viable osteocytes [ 54 ]. Other possible therapeutic options include BHQ880 and romosozumab. …

Prevention Of Skeletal Related Events In Multiple Myeloma: Focus On The RANK-L Pathway In The Treatment Of Multiple Myeloma.

More than 90% of patients with multiple myeloma (MM) have osteolytic bone lesions which increase the risk of skeletal-related events (SRE). The cytokine milieu in the bone marrow microenvironment (BMME) of MM plays a key role in myeloma bone disease by impairing the balance between osteoclastogenesis and osteoblastogenesis. This is orchestrated by the malignant plasma cell (MPC) with the ultimate outcome of MPC proliferation and survival at the expense of excess osteoclast activation resulting in osteolytic bone lesions. Prevention of SRE is currently accomplished by the inhibition of osteocla

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… induce osteocyte apoptosis which leads to increased RANKL and sclerosin secretion. … The former recruits and activates osteocytes while the later inhibits osteoblast function. 13 RANKL in particular is a key mediator of osteoclast formation, activation and survival. …