Journal of Bone and Mineral Research最新文献

Tumor-induced osteomalacia (TIO) is an ultrarare paraneoplastic syndrome of abnormal phosphate and vitamin D metabolism secondary to the overproduction of fibroblast growth factor 23 by small-sized mesenchymal tumors typically located in soft tissues and bone. The tumor has adverse effects on bone and patients complain of skeletal symptoms and in severe cases they suffer multiple devastating fractures. Specific features may characterize the histology of tumors located in bone with respect to those found in extra-skeletal sites. Indeed, the matrix may contain foci resembling primitive cartilage and osteoid. Light microscopy of bone biopsy samples reveal accumulation of osteoid due to thickening of osteoid seams and, if tetracyclines were sequentially administrated, fluorescence microscopy reveals prolongation of the mineralization lag time. Areal bone mineral density assessed by DXA is significantly lower at both the lumbar and femoral sites in patients with TIO and values of trabecular bone score are significantly reduced with respect to healthy individuals. Patients with TIO are also characterized by significant impairment in bone quality at both the trabecular and cortical compartment when evaluated by high-resolution peripheral quantitative computed tomography. Successful surgical removal of the causative tumor completely reverts biochemical abnormalities. Bone mineral density accrual is impressive in the short term at the central (spine and hip) level but may take longer to improve, together with microstructural parameters, at peripheral sites (radius and tibia). Future studies should address effects of long-term treatment on quality-of-life outcomes related to irreversible events, such as vertebral fractures. This is particularly important in patients with a heavy burden due to a long-standing disease.

Achondroplasia (ACH), the most common skeletal dysplasia in humans, is caused by gain-of-function mutations in fibroblast growth factor receptor 3 (FGFR3). Activation of FGFR3 and its downstream signaling pathways lead to disturbed chondrogenesis in achondroplasia. Nevertheless, the pathogenic mechanism of achondroplasia has yet not been fully elucidated. Previous studies have indicated that Fibroblast Growth Factor (FGF) and Bone Morphogenetic Protein (BMP) signaling may have opposing actions on the growth plate development. To clarify the crosstalk between FGFR3 and Activin Receptor-Like Kinase 3 (ALK3) signaling in achondroplasia, we generated caALK3col2-ACH mice expressing a constitutively active mutant of ALK3 in the chondrocytes of mice with ACH resulting from a Gly369Cys mutation in FGFR3. Unexpectedly, these mice exhibited a more severe chondrodysplasia phenotype than ACH mice, as evidenced by a greater decrease in chondrocyte proliferation and impaired hypertrophy of chondrocytes in the growth plates. These changes were correlated with an increased expression of p21 and activation of Extracellular Regulated protein Kinase (ERK)/ Mitogen-Activated Protein Kinase (MAPK) pathway. This study provides an in vivo genetic demonstration of the imbalanced interaction between the FGFR3 and ALK3 signaling pathways in the growth plate of caALK3col2-ACH mice, suggesting that the ERK/MAPK pathway play an essential role in growth plate chondrogenesis.

The polygenic risk score genetic quantitative ultrasound speed of sound (gSOS) was developed using machine learning algorithms in adults of European ancestry and associates with reduced odds of fracture in adults. We aimed to determine if gSOS was associated with bone health in children. Two observational studies of children were evaluated: (1) children enrolled in the Bone Mineral Density in Childhood Study (BMDCS) with genetic data (N = 1727); and (2) children with genetic data for research at the Children's Hospital of Philadelphia (CHOP; N = 10 301). Genetic variants were used to calculate gSOS and genetic ancestry. For the BMDCS, puberty stage, dietary calcium, physical activity and fracture accumulation (none or ≥ 1 fracture) were self-reported, height and weight were measured and BMI calculated. Areal bone mineral density (aBMD) of the lumbar spine, hip, radius, and whole body were assessed by dual energy X-ray absorptiometry and expressed as Z-scores. The CHOP study paired genetic data with documentation of fracture in the electronic health record (EHR). gSOS associated with higher aBMD Z-scores across 7 skeletal sites [eg, a 1 SD increase in gSOS associated with 0.17 (95% CI: 0.10-0.24) higher lumbar spine aBMD Z-score]. These associations were consistent for males and females, age, puberty stage, and lifestyle factors, and most consistent among children of European genetic ancestry. A 1 SD increase in gSOS associated with 24% reduced likelihood of self-reported fracture in the BMDCS (OR = 0.76, 95% CI: 0.66, 0.88) and a 12% reduced likelihood of a recorded fracture in the CHOP EHR (OR = 0.88; 95% CI: 0.82, 0.95). No sex or genetic ancestry differences were found. A higher gSOS score associated with higher aBMD at multiple skeletal sites and reduced odds of fracture in two independent pediatric samples. This genetic tool may have clinical utility to help enhance bone health in early life and protect against fracture across the lifespan.

Osteoporosis is the most prevalent metabolic bone disease globally, characterized by decreased bone mass and microarchitectural deterioration, leading to an increased risk of fractures. While its pathogenesis is multifactorial, including hormonal changes, aging and inflammatory processes, and thus far incompletely understood, recent advances in ion channel research have shed light on the importance of mechanosensitive ion channels as novel players in these pathophysiological processes. This perspective discusses the involvement of the mechanosensitive ion channels TREK-1, Piezo, and VRACs as potential novel pharmacological targets for the treatment of osteoporosis. TREK-1, a mechanosensitive K2P channel is important for maintaining the resting membrane potential in many cells, including osteoblasts and osteoclasts. K2P channels regulate osteoblast proliferation and differentiation, as well as osteoclast activity, potentially modulating bone remodeling in osteoporosis. Piezo channels influence osteoblast differentiation and osteoclast activity by modulating calcium influx, which is crucial for osteogenic signaling pathways such as Wnt/β-catenin and ERK1/2. Piezo1 activation promotes bone formation, while its deficiency leads to impaired osteogenesis and increased bone resorption. VRACs have been shown to be involved in osteoblast adaptation to mechanical stress and macrophage polarization, which indicates their importance for bone homeostasis. Chronic inflammation is a major contributor to osteoporosis progression. Evidence of ion channel involvement in this process has emerged in recent years. Specifically, macrophage function in osteoporosis seems to be linked to ion channel activity. Inflammatory polarization of macrophages is a key player in inflammation-induced bone loss and can be driven by mechanosensitive ion channels. Modulating these ion channels may provide therapeutic opportunities, as evidenced by studies showing that targeting TREK-1 and Piezo1 can alter macrophage polarization and reduce osteoclast-mediated bone resorption. Given the complexity of ion channel interactions in bone cells and their regulatory role in bone remodeling, understanding their precise function in osteoporosis is essential. Targeted modulation of mechanosensitive ion channels holds promise as a novel therapeutic approach to mitigate inflammation-driven bone loss and improve bone density. Further research into their role in osteoclasts and macrophage-driven bone degradation will aid in developing innovative osteoporosis treatments.

Abdominal aortic calcification (AAC), a marker of subclinical cardiovascular disease, has previously shown to be associated with low bone mineral density (BMD) and fracture. However, it remains unclear whether AAC is associated with trabecular bone score (TBS), a gray-level textural measure, or whether it predicts fracture risk independent of this measure. Here, we examined the cross-sectional association of AAC scored using a validated machine learning algorithm (ML-AAC24) with TBS, and their simultaneous associations with incident fractures in 7,691 individuals (93.4% women) through the Manitoba BMD Registry (mean age 75.3 years). The association between ML-AAC24 and TBS was tested using generalised linear regression. Cox proportional hazards models tested the simultaneous relationships of ML-AAC24 and TBS with incident fractures. At baseline, 41.3% of the study cohort had low (<2), 32.4% had moderate (2 to <6) and 26.3% had high (≥6) ML-AAC24. Compared to low ML-AAC24, high ML-AAC24 was associated with a 0.81% lower TBS in the multivariable-adjusted model. Independent of each other and multiple established fracture risk factors, ML-AAC24 and TBS were each associated with an increased risk of incident fractures. Specifically, high ML-AAC24 (HR 1.41 95%CI 1.15-1.73, compared to low ML-AAC24) and lower TBS (HR 1.13 95%CI 1.05-1.22, per SD decrease) were associated with increased relative hazards for any incident fracture. High ML-AAC24 and lower TBS were also associated with incident major osteoporotic fracture (HR 1.48 95%CI 1.18-1.87 and HR 1.15 95%CI 1.06-1.25, respectively) and hip fracture (HR 1.56 95%CI 1.05-2.31 and HR 1.25 95%CI 1.08-1.44, respectively). In conclusion, high ML-AAC24 is associated with lower TBS in older adults attending routine osteoporosis screening. Both measures were associated with incident fractures. The findings of this study highlight high ML-AAC24, seen in more than 1 in 4 of the study cohort, and lower TBS provide complementary prognostic information for fracture risk.