Journal of Bone and Mineral Metabolism最新文献

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.

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.

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.

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.

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.

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.