Journal of Bone and Mineral Research最新文献

We report two patients of east African ancestry with the same novel homozygous variant in the parathyroid hormone receptor type 1 (PTH1R). Both patients shared skeletal features including brachydactyly, extensive metacarpal pseudoepiphyses, elongated cone-shaped epiphyses, ischiopubic hypoplasia, deficient sacral ossification, suggestive of Eiken syndrome. Strikingly, both patients exhibited clinically manifest parathyroid hormone (PTH) resistance with hypocalcaemia and elevated serum phosphate levels. These laboratory and clinical abnormalities initially suggested pseudohypoparathyroidism, which is typically associated with GNAS abnormalities. In both patients, however, a homozygous novel PTH1R variant was identified (c.710 T > A; p.IIe237Asn, p.I237N) that is located in the second transmembrane helical domain. Previously, others have reported a patient with a nearby PTH1R mutation (D241E) who presented with similar clinical features, e.g. delayed bone mineralization as well as clinical PTH resistance. Functional analysis of the effects of both novel PTH1R variants (I237N- and D241E-PTH1R) in HEK293 reporter cells transfected with plasmid DNA encoding the wild-type or mutant PTH1Rs demonstrated increased basal cAMP signalling for both variants, with relative blunting of responses to both PTH and PTH-related peptide (PTHrP) ligands. The clinical presentation of PTH resistance and delayed bone mineralization combined with the functional properties of the mutant PTH1Rs suggest that this form of Eiken syndrome results from alterations in PTH1R-mediated signalling in response to both canonical ligands, PTH and PTHrP.

The cartilage growth plate is essential for maintaining skeletal growth; however, the mechanisms governing postnatal growth plate homeostasis are still poorly understood. Using approaches of molecular mouse genetics and spatial transcriptomics applied to formalin-fixed, paraffin-embedded (FFPE) tissues, we show that ADGRG6/GPR126, a cartilage-enriched adhesion G protein-coupled receptor (GPCR), is essential for maintaining slow-cycling resting zone cells, appropriate chondrocyte proliferation and differentiation, and growth plate homeostasis in mice. Constitutive ablation of Adgrg6 in osteochondral progenitor cells with Col2a1Cre leads to a shortened resting zone, formation of cell clusters within the proliferative zone, and an elongated hypertrophic growth plate, marked by limited expression of PTHrP but increased IHH signaling throughout the growth plate. Attenuation of Smoothened (SMO)-dependent hedgehog signaling restored the Adgrg6 deficiency-induced expansion of hypertrophic chondrocytes, confirming that IHH signaling can promote chondrocyte hypertrophy in a PTHrP-independent manner. In contrast, postnatal ablation of Adgrg6 in mature chondrocytes with AcanCreERT2, induced after the formation of the resting zone, does not affect PTHrP expression but causes an overall reduction of growth plate thickness marked by increased cell death specifically in the resting zone cells and a general reduction of chondrocyte proliferation and differentiation. Spatial transcriptomics reveals that ADGRG6 is essential for maintaining chondrocyte homeostasis by regulating osteogenic and catabolic genes in all the zones of the postnatal growth plates, potentially through positive regulation of SOX9 expression. Our findings elucidate the essential role of a cartilage-enriched adhesion GPCR in regulating cell proliferation and hypertrophic differentiation by regulation of PTHrP/IHH signaling, maintenance of slow-cycle resting zone chondrocytes, and safeguarding chondrocyte homeostasis in postnatal mouse growth plates.

Identifying individuals at risk for short-term fracture is essential to offer prompt beneficial treatment, especially since many fractures occur in those without osteoporosis by DXA-aBMD. We evaluated whether deficits in bone microarchitecture and density predict short-term fracture risk independent of the clinical predictors, DXA-BMD and FRAX. We combined data from eight cohorts to conduct a prospective study of bone microarchitecture at the distal radius and tibia (by HR-pQCT) and 2-year incidence of fracture (non-traumatic and traumatic) in 7327 individuals (4824 women, 2503 men, mean 69 ± 9 years). We estimated sex-specific hazard ratios (HR) for associations between bone measures and 2-year fracture incidence, adjusted for age, cohort, height and weight, and then additionally adjusted for femoral neck (FN) aBMD or FRAX for major osteoporotic fracture. Only 7% of study participants had FN T-score ≤ -2.5, whereas 53% had T-scores between -1.0 to -2.5 and 37% had T-scores ≥-1.0. Two-year cumulative fracture incidence was 4% (296/7327). Each SD decrease in radius cortical bone measures increased fracture risk by 38%-76% for women and men. After additional adjustment for FN-aBMD, risks remained increased by 28%-61%. Radius trabecular measures were also associated with 2-year fracture risk independently of FN-aBMD in women (HRs range: 1.21 per SD for trabecular separation to 1.55 for total vBMD). Decreased failure load was associated with increased fracture risk in both women and men (FN-aBMD ranges of adjusted HR = 1.47-2.42). Tibia measurement results were similar to radius results. Findings were also similar when models were adjusted for FRAX. In older adults, failure load and HR-pQCT measures of cortical and trabecular bone microarchitecture and density with strong associations to short-term fractures improved fracture prediction beyond aBMD and FRAX. Thus, HR-pQCT may be a useful adjunct to traditional assessment of short-term fracture risk in older adults, including those with T-scores above the osteoporosis range.

Background: Type 2 diabetes mellitus and lower weight are both associated with osteoporotic fractures, but the roles of variability and trajectory are less clear.1 The associations of these factors among older adults with dysglycemia, who are at highest risk of fracture, with fracture risk and bone mineral density (BMD) remains uncertain.

Methods: We followed 775 men and 1080 women from the Cardiovascular Health Study (mean age 77.4 years) with abnormal oral glucose tolerance testing in 1989-1990. We measured their weights yearly through 1994-1995 and derived intra-individual mean weight, weight slope, and weight variability. We also used growth mixture modelling to derive four latent body-mass index trajectories over time. We used Cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence intervals (CI) for subsequent hip fracture through 2015 and linear regression models to estimate cross-sectional associations with bone mineral density (BMD) of the hip.

Results: Each 10 kg higher mean weight was associated with a lower risk of subsequent hip fracture overall (HR 0.81; CI 0.70-0.94) and among women (HR 0.76; CI 0.64-0.91) and with higher BMD (P-value <0.001). Higher weight variability was directly associated with incident hip fracture among women (HR 1.18; CI: 1.03-1.35). Compared with a stable trajectory, a "progressive overweight" trajectory was associated with lower risk of hip fracture (HR 0.66; CI: 0.44-0.99). An uncommon trajectory of "accelerating obesity" was associated with higher BMD.

Conclusions: Among older adults with dysglycemia at high risk for fracture, lower mean weight is associated with higher fracture risk, but variability and trajectory may also contribute. These results highlight the complex effects of weight in older age.

The Physical Activity Scale for the Elderly (PASE) is a validated test to assess physical activity in older people. It has not been investigated if physical activity, according to PASE, is associated with fracture risk independently from the clinical risk factors (CRFs) in FRAX, bone mineral density (BMD), comorbidity, and if such an association is due to differences in physical performance or bone parameters. The purpose of this study was to evaluate if PASE score is associated with bone characteristics, physical function, and independently predicts incident fracture in 3014 75-80-yr-old women from the population-based cross-sectional SUPERB study. At baseline, participants answered questionnaires and underwent physical function tests, detailed bone phenotyping with DXA, and high-resolution peripheral quantitative CT. Incident fractures were X-ray verified. Cox regression models were used to assess the association between PASE score and incident fractures, with adjustments for CRFs, femoral neck (FN) BMD, and Charlson comorbidity index. Women were divided into quartiles according to PASE score. Quartile differences in bone parameters (1.56% for cortical volumetric BMD and 4.08% for cortical area, Q4 vs Q1, p = .007 and p = .022, respectively) were smaller than quartile differences in physical performance (27% shorter timed up and go test, 52% longer one leg standing time, Q4 vs Q1). During 8 yr (median, range 0.20-9.9) of follow-up, 1077 women had any fracture, 806 a major osteoporotic fracture (MOF; spine, hip, forearm, humerus), and 236 a hip fracture. Women in Q4 vs. Q1 had 30% lower risk of any fracture, 32% lower risk of MOF, and 54% lower risk of hip fracture. These associations remained in fully adjusted models. In conclusion, high physical activity was associated with substantially better physical function and a lower risk of any fracture, MOF and hip fracture, independently of risk factors used in FRAX, FN BMD, and comorbidity.

Mitochondria in osteoblasts have been demonstrated to play multiple crucial functions in bone formation from intracellular adenosine triphosphate production to extracellular secretion of mitochondrial components. The present review explores the current knowledge about mitochondrial biology in osteoblasts, including mitochondrial biogenesis, bioenergetics, oxidative stress generation, and dynamic changes in morphology. Special attention is given to recent findings, including mitochondrial donut formation in osteoblasts, which actively generates mitochondrial-derived vesicles (MDVs), followed by extracellular secretion of small mitochondria and MDVs. We also discuss the therapeutic effects of targeting osteoblast mitochondria, highlighting their potential applications in improving bone health.