Shimada M, Tsuyama T, Yoshimura N
… +30 more, Tateyama M, Matsunaga H, Homma F, Dainobu K, Tian X, Takata S, Takata K, Tanimura S, Shibata Y, Maeda K, Kawakami J, Arima T, Karasugi T, Tokunaga T, Sato H, Masuda T, Hisanaga S, Kai Y, Karata S, Goshogawa H, Tajiri R, Yamada H, Uehara Y, Nakamura T, Yugami M, Sugimoto K, Yonemitsu R, Tanoue H, Yamagata K, Miyamoto T
J Bone Miner Metab
· 2026 Mar · PMID 41872383
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INTRODUCTION: Giant cell tumor of bone (GCTB) induces overproduction of bone-resorbing osteoclasts through receptor activator of nuclear factor kappa B ligand (RANKL), leading to bone resorption and destruction. Conseque...INTRODUCTION: Giant cell tumor of bone (GCTB) induces overproduction of bone-resorbing osteoclasts through receptor activator of nuclear factor kappa B ligand (RANKL), leading to bone resorption and destruction. Consequently, denosumab, a neutralizing antibody against RANKL (a cytokine essential for osteoclast induction), is used to treat patients with GCTB. However, the activity of bone formation in GCTB remains poorly understood. Here, we show that GCTB antagonizes bone formation by expressing WNT5B, which inhibits bone formation. MATERIALS AND METHODS: Co-culture of NCC-GCTB1-C1 (GCTB1s), a human GCTB cell line, with human adipose-derived stem cells (ADSCs) was performed with osteoblast induction medium. To identify the inhibitors of osteoblast differentiation, we reanalyzed the single-cell RNA sequencing data that was previously published. In addition, we performed spatial transcriptome analysis (Visium) against the section of paraffin block of GCTB. The targeted protein was knocked out using CRISPR/Cas9 and co-culture was performed. RESULTS: Co-culture of GCTB1s with ADSCs significantly inhibited mineralization of ADSCs. Reanalysis of single-cell RNA sequencing data indicated that GCTB tumors express WNT5B, and we observed that GCTB1s express WNT5B. We then knocked out WNT5B in GCTB1s using CRISPR/Cas9 and co-cultured them with ADSCs and observed significant rescue of mineralization in ADSCs relative to ADSCs cultured with GCTB1s expressing WNT5B. We also show that ADSC supernatants induce mineralization of GCTB1s. CONCLUSION: These studies indicate that GCTB not only induces osteoclasts, but also possesses activity that inhibits bone formation.
J Bone Miner Metab
· 2026 Mar · PMID 41872382
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PURPOSE: Framed as the "geography" of skeletal stem cells (SSCs), this review aims to synthesize how developmental stages and local niche cues determine SSC identity and function. Ultimately, it seeks to provide a compre...PURPOSE: Framed as the "geography" of skeletal stem cells (SSCs), this review aims to synthesize how developmental stages and local niche cues determine SSC identity and function. Ultimately, it seeks to provide a comprehensive conceptual basis for understanding skeletal development and regeneration. RESULT: By moving beyond early in vitro concepts of colony-forming unit fibroblasts (CFU-Fs), recent advances in in vivo lineage tracing, clonal analyses, and spatial/single-cell omics have revealed pronounced heterogeneity within marrow SSCs and identified anatomically distinct populations in the cartilage, perichondrium, and periosteum (both fibrous and cambium layers). These specific compartments display a context-dependent division of labor: perichondrial and periosteal SSCs drive bone growth and fracture healing; cartilage-embedded progenitors maintain articular and growth-plate tissues; and marrow stromal SSCs primarily support steady-state bone remodeling and hematopoiesis, while responding variably after injury. CONCLUSION: The spatial and temporal geography of SSCs dictates their specialized roles across development, homeostasis, and repair. Mapping these anatomically distinct populations provides a crucial conceptual framework for understanding skeletal biology and developing targeted regenerative therapies.
Wang Y, Xia L, Xiao Y
… +4 more, Wu M, Zhang R, Rexiti P, Zhang H
J Bone Miner Metab
· 2026 Mar · PMID 41870631
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INTRODUCTION: Apoptosis plays a significant role in osteoporosis (OP), yet a causal relationship between apoptosis gene expressions and OP remains unexplored. This study applies an integrated multi-omics analysis to esta...INTRODUCTION: Apoptosis plays a significant role in osteoporosis (OP), yet a causal relationship between apoptosis gene expressions and OP remains unexplored. This study applies an integrated multi-omics analysis to establish causality between them, offering clinical treatment and prediction insights. MATERIALS AND METHODS: Apoptosis-related genes are sourced from GeneCards, and 6 transcriptomic datasets from the cells in the circulation are obtained from GEO. Meta-analysis integrated differentially expressed apoptosis-related genes (DEGs) from the above 6 datasets. Causality between gene expressions, epigenetic changes, and OP is examined using OP genome-wide association study (GWAS), plasma expression quantitative trait loci (eQTL), and methylation quantitative trait loci (mQTL) data, while analysis of skeletal muscle eQTL and OP GWAS data is conducted. External validation is performed with the UK Biobank datasets. RESULTS: Meta-analysis of 6 GEO datasets identified 384 DEGs, including 78 apoptosis-related genes. The three-step analysis indicates 8 candidate causal genes in blood, including MAP3K3, DPP8, RPL3, PPP2CA, CD86, LRRFIP1, TRAP1, and DUSP6, with LRRFIP1 influenced by four methylation sites. Analysis of skeletal muscle data reveals 4 causal genes, including SIPA1L3, PDLIM7, CTNNB1, and DPP8. Among apoptosis-related genes causally linked to OP in both circulation and skeletal muscle, LRRFIP1 was validated based on methylation-associated regulation and demonstrated consistent, reproducible expression patterns. CONCLUSIONS: This study uses a multi-omics strategy to clarify the roles of apoptosis-related gene expressions and their corresponding methylation in OP, providing targets and a basis for early diagnosis, personalized treatment, and monitoring of OP.
J Bone Miner Metab
· 2026 Mar · PMID 41832918
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BACKGROUND: The bone extracellular matrix (ECM) is no longer viewed as a passive scaffold, but as an instructive niche that actively governs skeletal development, homeostasis, and regeneration. It functions beyond mechan...BACKGROUND: The bone extracellular matrix (ECM) is no longer viewed as a passive scaffold, but as an instructive niche that actively governs skeletal development, homeostasis, and regeneration. It functions beyond mechanical and structural support, serving as a solid-phase signaling hub that sequesters and releases morphogens such as TGF-β, BMPs, and Wnt ligands, thereby coupling matrix remodeling to mesenchymal stromal cell differentiation, osteogenic progenitor expansion, and late-stage mineralization. OBJECTIVE: In this review, we summarize the current understanding of how collagens, glycoproteins, and proteoglycans assemble into a dynamic, viscoelastic composite with multiscale porosity and pronounced stiffness gradients that shape skeletal tissue. We discuss how these physical and biochemical properties are continuously shaped by ECM-modifying enzymes, including lysyl oxidases (LOX/LOXLs), transglutaminases, MMPs, and ADAMTS proteases, and how the ECM is further regulated by non-enzymatic glycation in aging and diabetes. We also examine the role of osteocytes as orchestrators of ECM turnover, emphasizing perilacunar and canalicular remodeling and the PHEX/MEPE/ASARM axis in coordinating mineralization and phosphate homeostasis. In the context of regeneration, we summarize emerging roles for matricellular proteins such as periostin and tenascin-C in coordinating regenerative programs. The bone ECM is a dynamically regulated structure whose biochemical and physical properties are continuously modified by enzymatic and non-enzymatic processes. Osteocytes play a central role in orchestrating ECM turnover and mineralization. Matricellular proteins, particularly osteolectin (OLN), exemplify how matrix-associated ligands can activate Wnt signaling through integrin α₁β₁. We argue that systematic mining of the bone ECM-secreted proteome will uncover additional cell-type-restricted anabolic cues and therapeutic opportunities for genetic dysplasias, fracture non-unions, osteoporosis, and metabolic bone fragility.
Nozoe A, Ohata Y, Fujiwara M
… +10 more, Yamamoto K, Nambara T, Nakano C, Miyagawa K, Kogo M, Taketani T, Kubota T, Kitabatake Y, Tanaka S, Ozono K
J Bone Miner Metab
· 2026 May · PMID 41831016
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INTRODUCTION: Hypophosphatasia (HPP) is a rare bone disease caused by pathological variants of ALPL. While hypomineralization of dentin and odontoblast (OD) differentiation defects are known to occur in HPP, the underlyi...INTRODUCTION: Hypophosphatasia (HPP) is a rare bone disease caused by pathological variants of ALPL. While hypomineralization of dentin and odontoblast (OD) differentiation defects are known to occur in HPP, the underlying pathophysiology remains poorly understood. MATERIALS AND METHODS: We generated induced pluripotent stem cell (iPSC) lines from patients with perinatal severe HPP (Perinatal) and then isogenic (Rescued) and odontohypophosphatasia type (Odonto) lines using gene editing. These three HPP-iPSC lines were differentiated into OD-like cells via mesenchymal stem cells derived from neural crest cells. The characteristics of the OD-like cells were assessed. RESULTS: Rescued-OD-like cells demonstrated mineralization ability, increased microtubule-associated protein tau (MAPT) expression, and unidirectional cell processes, while these characteristics were impaired in Perinatal- and Odonto-OD-like cells. These findings suggest that these features are associated with reduced ALP activity. Notably, neurofilament light chain (NEFL) expression was enhanced in Odonto-OD-like cells compared to Perinatal- and Rescued-OD-like cells. NEFL knockdown partially rescued cell process elongation in Odonto-OD-like cells without affecting alkaline phosphatase activity, while NEFL overexpression inhibited cell process elongation in Rescued-OD-like cells. CONCLUSIONS: Enhanced expression of NEFL in Odonto-OD-like cells negatively correlates with OD morphology and may be relevant to odontoblast morphological abnormalities associated with odontohypophosphatasia; however, generalization to other odonto-HPP genotypes requires additional patient-derived lines.
J Bone Miner Metab
· 2026 May · PMID 41817734
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INTRODUCTION: This study aimed to systematically evaluate the association between the Healthy Eating Index (HEI-2020), the Alternative Healthy Eating Index (AHEI), and the risk of osteoporotic fractures based on the Nati...INTRODUCTION: This study aimed to systematically evaluate the association between the Healthy Eating Index (HEI-2020), the Alternative Healthy Eating Index (AHEI), and the risk of osteoporotic fractures based on the National Health and Nutrition Examination Survey (NHANES) database. MATERIALS AND METHODS: We included 13,541 participants from NHANES data, of whom 1,646 experienced osteoporotic fractures. Diet quality was assessed using HEI-2020 and AHEI scores. Weighted multivariable logistic regression, restricted cubic spline (RCS) analysis, and subgroup analyses were applied to evaluate the relationship between HEI-2020, AHEI, and osteoporotic fracture risk. RESULTS: After full adjustment for confounding factors, each 1-point increase in HEI-2020 and AHEI scores was associated with a 1.5% (OR = 0.985, 95% CI: 0.978-0.992) and 1.3% (OR = 0.987, 95% CI: 0.980-0.994) reduction in osteoporotic fracture risk, respectively. RCS analysis indicated that both HEI-2020 (p for nonlinear = 0.2911) and AHEI (p for nonlinear = 0.3951) were linearly and inversely associated with osteoporotic fracture risk (all P overall < 0.0001). Subgroup analyses showed that this association remained consistent across populations stratified by sex, age, BMI, smoking status, hypertension, diabetes, and cardiovascular disease, with no significant interactions observed. Sensitivity analyses excluding participants who reported the use of prescription medications for hypertension or diabetes yielded results consistent with the primary analyses after multivariable adjustment. CONCLUSION: This study systematically showed a significant inverse association between HEI-2020, AHEI, and osteoporotic fracture risk. The findings suggest that improving diet quality may be a feasible strategy for preventing osteoporotic fractures, with broad population applicability and public health implications.
J Bone Miner Metab
· 2026 Mar · PMID 41741664
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BACKGROUND: Hematopoietic stem cells (HSCs) are the lifelong source of hematopoietic cells, maintained within the specialized microenvironment of the bone marrow. A central question remains regarding the mechanisms that...BACKGROUND: Hematopoietic stem cells (HSCs) are the lifelong source of hematopoietic cells, maintained within the specialized microenvironment of the bone marrow. A central question remains regarding the mechanisms that regulate HSC maintenance. Functional studies have advanced our knowledge of the HSC niche, which consists of perivascular stromal, skeletal, and endothelial cells. Understanding the HSC niche is particularly important in the context of myeloablation which disrupts both the hematopoietic cells and their supporting microenvironment. As a clinical intervention, myeloablation followed by HSC transplantation is a well-established treatment option that has been shown to improve prognosis and increase survival in patients. These positive outcomes result from the reconstitution of the hematopoietic system by transplanted HSCs with the support of the regenerated microenvironment. OBJECTIVE: Recent studies have made significant progress in understanding the plasticity of the bone marrow microenvironment. This review provides an overview of recent findings on the HSC niche during homeostasis and after myeloablative stress. CONCLUSION: Despite the advances made, it is still unclear how the bone marrow microenvironment adjusts and regenerates after stress. Further advances in understanding HSC niche regeneration could have important implications for patient care.
J Bone Miner Metab
· 2026 Mar · PMID 41711876
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INTRODUCTION: Skeletal stem cells (SSCs) and their lineage derivatives play essential roles in bone development, maintenance, and regeneration. In addition to their physiological functions, SSCs have been implicated in p...INTRODUCTION: Skeletal stem cells (SSCs) and their lineage derivatives play essential roles in bone development, maintenance, and regeneration. In addition to their physiological functions, SSCs have been implicated in primary bone tumor development and bone metastasis. Recent lineage-tracing studies have identified fibroblast growth factor receptor 3 (Fgfr3)-positive endosteal stem cells as a distinct SSC population residing along the endosteal surface of juvenile long bones. METHODS: This review comprehensively synthesizes previous studies on skeletal stem cells and their lineage derivatives, integrating findings from lineage-tracing approaches, genetically engineered mouse models, and bone tumor models. By organizing current knowledge of SSC hierarchy and differentiation, we provide a framework for understanding how SSC-derived lineages contribute to both bone homeostasis and cancer-related processes. RESULTS: Fgfr3 endosteal stem cells give rise to osteoblasts and C-X-C motif chemokine ligand 12 (Cxcl12)-positive bone marrow reticular stromal cells that organize the hematopoietic niche. In temporally controlled Fgfr3-creER; Trp53 models, Trp53 deletion within the endosteal stem cell niche rapidly induces high-penetrance osteosarcoma, indicating that this niche is particularly vulnerable to malignant transformation. Beyond tumor initiation, SSC-derived Cxcl12-expressing stromal cells differentiate into cancer-associated fibroblasts that promote metastatic colonization, angiogenesis, and immunosuppression in bone. CONCLUSION: Collectively, these findings highlight Fgfr3 endosteal stem cells as candidate cells of origin for osteosarcoma and underscore the dual role of SSC-derived lineages in both tumor initiation and progression. Targeting SSC-derived endosteal niches may provide new therapeutic opportunities for bone malignancies.
J Bone Miner Metab
· 2026 Mar · PMID 41711875
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BACKGROUND: Bone is a multifunctional organ that provides structural support and hosts the bone marrow, a key site for hematopoiesis and systemic homeostasis. These dual features have long attracted the attention of both...BACKGROUND: Bone is a multifunctional organ that provides structural support and hosts the bone marrow, a key site for hematopoiesis and systemic homeostasis. These dual features have long attracted the attention of both bone biologists and hematologists. Each field has pursued the identification of stem-like cells responsible for hard tissue formation and the regulatory microenvironment/niche that supports hematopoietic stem cells (HSCs), which give rise to all blood cell lineages. Converging advances in bone and hematopoietic biology have led to the identification of skeletal stem/progenitor cells (SSPCs), a multifunctional population that gives rise to osteolineage cells and serves as a principal component of the HSC niche. This landmark discovery was largely enabled by Cre/loxP-based genetic mouse models. Among them, the leptin receptor (LepR)-Cre system has become one of the most widely used tools in skeletal stem cell research worldwide. OBJECTIVE: In this review, we summarize the historical background and recent advances in SSPC research, specifically LepR SSPCs, highlighting their function and lineage plasticity during development, adolescence, aging, and fracture healing. Advanced genetic labeling-based studies and single-cell transcriptomics unveiled the fate, dynamics and indispensible roles of LepR⁺ SSPCs under both homeostatic and pathological conditions.
J Bone Miner Metab
· 2026 Mar · PMID 41706167
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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 chang...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-immune equilibrium. RESULTS: Aging was found to skew the immune environment, exacerbating bone destruction. The review identifies emerging immunomodulatory strategies to rejuvenate bone healing, such as targeting senescent cells (senolytics) and inflammatory cytokines to modulate the immune microenvironment. CONCLUSION: Addressing the unique challenges of the aging population is critical for regenerative dentistry. Future research must bridge current gaps to translate immunomodulatory insights into clinical therapies for improving alveolar bone regeneration in older patients.
J Bone Miner Metab
· 2026 May · PMID 41706166
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INTRODUCTION: This study aimed to compare the risk of osteoporosis between sodium-glucose cotransporter 2 inhibitors (SGLT2is) and thiazolidinediones (TZDs) in older women with type 2 diabetes (T2D). MATERIALS AND METHOD...INTRODUCTION: This study aimed to compare the risk of osteoporosis between sodium-glucose cotransporter 2 inhibitors (SGLT2is) and thiazolidinediones (TZDs) in older women with type 2 diabetes (T2D). MATERIALS AND METHODS: We conducted a population-based cohort study using the Korean National Health Insurance data. This study included women aged ≥ 55 years with T2D who used SGLT2is or TZDs between January 2022 and December 2023. Inverse probability of treatment weighting (IPTW) using propensity scores was employed to balance baseline covariates between SGLT2i and TZD users. Adjusted hazard ratios (aHRs) were estimated using multivariable weighted Cox proportional hazards models. RESULTS: Among 8,304 and 2,147 patients who initiated SGLT2i or TZD therapy, respectively, 5,358 SGLT2i and 1,169 TZD users were included in the Cox model. SGLT2i use was associated with a lower risk of osteoporosis than TZD use (aHR, 0.78; 95% confidence interval [CI] 0.69-0.89). The incidence rates of osteoporosis were 6.7 (95% CI 6.0-7.4) and 9.1 (95% CI 7.4-10.9) per 100 person-years for SGLT2i and TZD users, respectively. Compared with non-use, use of proton pump inhibitors (PPIs) for 270-364 days and metformin in the year prior to follow-up were associated with higher osteoporosis risk (aHRs 1.25 [95% CI 1.01-1.55] and 1.31 [95% CI 1.10-1.55], respectively). CONCLUSION: Despite concerns about a potential association between SGLT2is and reduced bone mineral density, our findings suggest a lower risk of osteoporosis with SGLT2is than with TZDs among older, likely postmenopausal women with T2D.
Imanishi Y, Hirakawa T, Haruyama W
… +12 more, Tsushida K, Sakai M, Kitayama T, Kawata T, Donoue E, Inoue K, Kobayashi I, Nagata Y, Kurajoh M, Shoji T, Arnold A, Emoto M
J Bone Miner Metab
· 2026 May · PMID 41701341
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BACKGROUND: Evocalcet is an allosteric modulator of the calcium-sensing receptor (CaSR) that effectively suppresses parathyroid hormone (PTH) secretion in both primary and secondary hyperparathyroidism. However, its effe...BACKGROUND: Evocalcet is an allosteric modulator of the calcium-sensing receptor (CaSR) that effectively suppresses parathyroid hormone (PTH) secretion in both primary and secondary hyperparathyroidism. However, its effects on the PTH-calcium setpoint and parathyroid cell proliferation remain unclear. METHODS: We investigated these effects using the PC mouse model of primary hyperparathyroidism, which is characterized by parathyroid-targeted cyclin D1 overexpression . Evocalcet was administered orally at a dose of 0.025 mg/g diet. The PTH-calcium setpoint was evaluated, and the antiproliferative effect of evocalcet on parathyroid cells was assessed using 5-bromo-2'-deoxyuridine (BrdU) incorporation assays. The effects of evocalcet were compared with those of cinacalcet. Expression levels of the vitamin D receptor (VDR) and CaSR in parathyroid glands were also examined. RESULTS: Evocalcet significantly reduced the PTH-calcium setpoint in PC mice, restoring it to levels comparable to those observed in wild-type controls. Evocalcet treatment markedly decreased the proportion of BrdU-positive parathyroid cells, indicating suppression of parathyroid cell proliferation. This antiproliferative effect was comparable to that observed with cinacalcet. Neither evocalcet nor cinacalcet altered VDR or CaSR expression in the parathyroid glands. CONCLUSIONS: Evocalcet, similar to cinacalcet, lowers the PTH-calcium setpoint and inhibits parathyroid cell proliferation in a mouse model of primary hyperparathyroidism. These findings suggest that evocalcet may not only reduce PTH secretion but also attenuate disease progression in hyperparathyroidism.
Li H, Yang Z, Li M
… +8 more, Yang H, Liu D, Bi Y, Dai X, Chen X, Miao L, Yang F, Chen Z
J Bone Miner Metab
· 2026 May · PMID 41701340
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INTRODUCTION: Recent studies have linked gut microbiota composition to osteonecrosis, but the causal relationship remains unclear. Clarifying this relationship is clinically important because osteonecrosis currently lack...INTRODUCTION: Recent studies have linked gut microbiota composition to osteonecrosis, but the causal relationship remains unclear. Clarifying this relationship is clinically important because osteonecrosis currently lacks early biomarkers and etiology-targeted therapies; if causal, the gut microbiome would offer a readily modifiable intervention target. METHODS: We conducted a two-sample Mendelian randomization analysis to explore this relationship. Exposure data were sourced from the MiBioGen consortium (N = 18,340), while outcome data on osteonecrosis were obtained from FinnGen (N = 392,580). The Inverse Variance Weighted method was used as the primary analytical approach, supplemented by comprehensive sensitivity analyses to assess the robustness of our findings. RESULTS: Our analysis screened 196 microbial taxa and identified seven taxa associated with osteonecrosis risk in European populations. Protective effects were noted for the genus Odoribacter (OR = 0.579; P = 0.027) and family Alcaligenaceae (OR = 0.703; P = 0.049). Conversely, increased risk was linked to the genus Eubacterium fissicatena group (OR = 1.272; P = 0.046), genus Bifidobacterium (OR = 1.372; P = 0.038), order Bifidobacteriales (OR = 1.412; P = 0.023), family Bifidobacteriaceae (OR = 1.412; P = 0.023) and phylum Actinobacteria (OR = 1.750; P = 0.001). Sensitivity analyses confirmed the robustness of these findings, with no evidence of pleiotropy or heterogeneity. CONCLUSION: This study establishes a causal link between gut microbiota composition and osteonecrosis, suggesting that gut microbiota may be a modifiable factor in its pathogenesis. Further research is needed to elucidate underlying mechanisms and evaluate microbiota-targeted interventions for prevention and treatment.
J Bone Miner Metab
· 2026 Mar · PMID 41697318
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Bone is a highly vascularized organ, and the vasculature in bone not only delivers oxygen and nutrients but also helps determine when and where bone forms, how the marrow is organized, and how hematopoietic stem cells (H...Bone is a highly vascularized organ, and the vasculature in bone not only delivers oxygen and nutrients but also helps determine when and where bone forms, how the marrow is organized, and how hematopoietic stem cells (HSCs) are maintained. Over the past decade, research has shifted from a single, uniform view of bone vessels to site- and stage-specific endothelial programs along the metaphysis-diaphysis-epiphysis axis of long bones. Local endothelial identity and hemodynamic signals coordinate angiogenesis with osteogenesis and shape the marrow niche. These programs also shift with aging. This review summarizes the recent advances in these endothelial programs and their roles in bone growth and hematopoiesis. Considering the vasculature as an active driver of skeletal integrity and hematopoietic function suggests strategies to strengthen bone, reduce skeletal fragility, and sustain hematopoiesis. This framework provides a roadmap for future studies and clinical translation.
Noroozzadeh M, Changaei M, Farhadi-Azar M
… +2 more, Mousavi M, Ramezani Tehrani F
J Bone Miner Metab
· 2026 May · PMID 41691554
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INTRODUCTION: Polycystic ovary syndrome (PCOS) has been associated with conflicting effects on bone mass, underscoring the need for deeper investigation into its impact on skeletal health. This study aimed to assess the...INTRODUCTION: Polycystic ovary syndrome (PCOS) has been associated with conflicting effects on bone mass, underscoring the need for deeper investigation into its impact on skeletal health. This study aimed to assess the expression of osteoporosis-related genes in femoral bone, alongside hormonal profile (bone-related hormones) alterations, across aging in a rat model of PCOS compared to controls. MATERIALS AND METHODS: Femoral bone RNA was extracted from rat model of PCOS and controls (n = 10-13 per group) at 3, 10, and 18 months of age. The expression of IL-11, DKK1, RANKL, AKT1, IGF-1, EphB4, STAT3, and CTNNB1 genes was quantified via Real-Time PCR. Concurrently, serum levels of Anti-Mullerian Hormone (AMH), calcitonin, cortisol, total testosterone (TT), and vitamin D3 were measured using ELISA. RESULTS: A significantly elevated expression of IL-11, DKK1, RANKL, AKT1, and IGF-1 genes, accompanied by a decreased expression of EphB4 and STAT3 in the femoral bone of rat model of PCOS compared to controls, was observed. Additionally, rat model of PCOS exhibited higher serum levels of AMH, cortisol, and TT, whereas calcitonin and vitamin D3 levels were decreased. CONCLUSIONS: These molecular and hormonal alterations highlight a dysregulation in bone metabolism associated with PCOS and suggest that PCOS may represent a substantial risk factor for osteoporosis later in life. The employed rat model thus offers a valuable platform for elucidating the cellular and molecular mechanisms contributing to bone mass disorders in PCOS, facilitating the development of targeted therapeutic strategies.