Journal of Bone and Mineral Research最新文献

Bone undergoes life-long remodelling, in which disorders of bone remodelling could occur in many pathological conditions including osteoporosis. Understanding the cellular metabolism of osteoclasts is key to developing new treatments for osteoporosis, a disease that affects over 200 million women worldwide per annum. We found that human osteoclast differentiation from peripheral blood mononuclear cells (PBMCs) derived from 8 female patients is featured with a distinct gene expression profile of mitochondrial biogenesis. Elevated mitochondrial membrane potential (MMP, Δψm) was also observed in RANKL-induced osteoclasts. Interestingly, the gene pathways of heme synthesis and metabolism were activated upon RANKL stimulation, featured by a transcriptomic profiling in murine cells at a single-cell resolution, which revealed a stepwise expression pattern of heme-related genes. The real-world human data also divulges potential links between heme-related genes and bone mineral density. Heme is known to have a role in the formation of functional mitochondrial complexes that regulate MMP. Disruption of heme biosynthesis via genetically silencing Ferrochelatase or a selective inhibitor, N-methyl Protoporphyrin IX (NMPP), demonstrated potent inhibition of osteoclast differentiation, with a dose-dependent effect observed in NMPP treatment and a substantial efficacy even at a single dose. In vivo study further showed the protective effect of NMPP on ovariectomy-induced bone loss in female mice. Collectively, we found that RANKL-mediated signaling regulated mitochondrial formation and heme metabolism to synergistically support osteoclastogenesis. Inhibition of heme synthesis impaired osteoclast formation and reversed excessive bone loss, representing a new therapeutic target for metabolic skeletal disorders.

Denosumab is a highly effective treatment for osteoporosis, and its long-term use is associated with incremental gains in bone mineral density (BMD) and sustained fracture risk reduction. Stopping denosumab, however, results in rebound increase in bone turnover, loss of treatment-associated BMD gains, and in the worst case, spontaneous vertebral fractures (VFs). Insights into the risk factors and the underlying mechanisms for rebound-associated bone loss and true incidence of rebound VFs are emerging. Conventional strategies using bisphosphonates to mitigate post-denosumab rebound display mixed success. Bisphosphonates may preserve bone density following short-term denosumab but the optimal sequential approach after longer-term denosumab remains elusive. Patients at particular risk of are those with prevalent VFs or greater on-treatment BMD gains. To greater understand these risks and strategies to preserve bone after denosumab, an emerging body of translational and pre-clinical work is shedding new light on the biology of RANKL inhibition and withdrawal. Discovering an effective "exit strategy" to control rebound bone turnover and avoid bone loss after denosumab will improve confidence amongst patients and clinicians in this highly effective and otherwise safe treatment for osteoporosis. This perspective characterizes the clinical problem of post-denosumab rebound, provides a comprehensive update on human studies examining the use of bisphosphonates following denosumab and explores mechanistic insights from pre-clinical studies that will be critical in the design of definitive human trials.

Alveolar bone supports and anchors teeth. The parathyroid hormone-related protein (PTHrP) pathway plays a key role in alveolar bone biology. Salt inducible kinases (SIKs) are important downstream regulators of PTH/PTHrP signaling in the appendicular skeleton, where SIK inhibition increases bone formation and trabecular bone mass. However, the function of these kinases in alveolar bone remains unknown. Here, we report a critical role for SIK2/SIK3 in alveolar bone development, homeostasis, and socket healing after tooth extraction. Inducible SIK2/SIK3 (Ubq-creERt;Sik2f/f;Sik3f/f) deletion led to dramatic alveolar bone defects without changes in tooth eruption. Ablating these kinases impairs alveolar bone formation due to disrupted osteoblast maturation, a finding associated with ectopic periostin expression by fibrous cells in regions of absent alveolar bone at steady state and following molar extraction. Notably, this phenotype is the opposite of the increased trabecular bone mass observed in long bones following SIK2/SIK3 deletion. Distinct phenotypic consequences of SIK2/SIK3 deletion in appendicular versus craniofacial bones prompted us to identify a specific transcriptomic signature in alveolar versus long bone osteoblasts. Thus, SIK2/SIK3 deletion illuminates a key role for these kinases in alveolar bone biology and highlights the emerging concept that different osteoblast subsets utilize unique genetic programs. (192/300).

Aim: To determine the effects of roxadustat on calcification when treating renal anemia in end-stage kidney disease (ESKD) patients.

Methods: A prospective cohort study enrolled participants with ESKD that either received roxadustat or no roxadustat treatment. The primary outcome was the change in the degree of hydroxyapatite (HAP) crystals deposition. The secondary outcome was calcification propensity, a measure of calcification, allowing an evaluation of the conversion process from primary to secondary calciprotein particles.

Results: A total of 205 patients were enrolled, and 187 (91.2%) completed follow-up for inclusion in the analysis and were divided into the roxadustat group (n = 92) and the control group (n = 95) based on whether or not they were taking roxadustat regularly over a 6-month period. After roxadustat administration for 6 months, patients exhibited increases in total red blood cell counts, hematocrit, hemoglobin, calcium, total ferritin binding, iFGF23, SPP24, and calcification propensity relative to pre-treatment levels. No significant differences were observed in patients who were not treated with roxadustat. The deposition degree of HAP crystals increased by 5% and 0.01% following treatment with roxadustat in the roxadustat group and control group, respectively. Linear regression analysis found that the use of roxadustat was an independent risk factor for calcification propensity and changes in the degree of HAP crystals deposition.

Conclusion: Roxadustat treatment may increase iFGF23, SPP24, and calcification propensity in patients with ESKD when treating these patients for renal anemia. Therefore, the clinicians should aware of this risk when treating patients with PHIs.

The abnormal mechanical stress has been considered as a major contributor of temporomandibular joint osteoarthritis (TMJOA), but the mechanism by which it leads to the degeneration of condylar cartilage remains elusive. The double-stranded (dsDNA)-sensing cGAS/STING pathway serves as a response mechanism in many sterile inflammatory responses. In the present study, we found that mechanical stress exerted on condyle chondrocytes induced dsDNA leakage from mitochondria to cytoplasm to activate STING. Upon activation, STING exacerbated cartilage degradation by suppressing the anabolism of cartilage extracellular matrix (ECM) and accelerating the catabolic activity. Furthermore, the promoted glycolysis in chondrocytes was identified as a central mechanism in the onset of TMJOA, with critical rate-limiting enzymes downstream of STING. Our study not only establishes an important link between the intrinsic TMJOA suppressor activity of STING and chondrocyte metabolism, but also has critical implications for the development of STING-targeted therapeutic modalities of TMJOA.