Journal of Bone and Mineral Metabolism最新文献

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.

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^fl/fl 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.

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.

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.

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.

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.

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.

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.

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.