To investigate whether latent epigenetic ageing is causally associated with bone mineral density using Mendelian randomization and to identify monocyte-specific genes potentially mediating this relationship. A latent epigenetic ageing factor was constructed from four DNA methylation clocks (GrimAge, Hannum, PhenoAge, and intrinsic epigenetic age acceleration) using Genomic structural equation modelling. Causal effects on heel estimated bone mineral density (eBMD; N = 426,824) were tested by two-sample Mendelian randomization (MR) and the pleiotropy-robust CAUSE framework. Monocyte-specific mediating genes were identified through single-cell PrediXcan with OneK1K prediction models, Bayesian colocalization, SMR-HEIDI, and causal transcriptome-wide association study fine-mapping. Functional consequences of prioritized variants were characterized using AlphaGenome, and key candidates were examined at the protein level in RANKL-induced THP-1 osteoclast differentiation as a first step toward validation in primary human monocyte-derived osteoclasts. Forward MR provided evidence consistent with a potential causal association between the latent ageing factor and eBMD (inverse-variance weighted β = 0.067, P = 3.6 × 10−4), with concordant sensitivity and CAUSE estimates; reverse MR was null. Single-cell PrediXcan revealed monocyte enrichment and an 11-gene pleiotropic core set. Colocalization and SMR-HEIDI converged on IFT80 (posterior probability of hypothesis 4 = 0.769) and TRIM59 (posterior probability of hypothesis 4 = 0.886) at chromosome 3. Causal transcriptome-wide association study fine-mapping nominated 45 high-confidence eBMD genes, independently confirming both IFT80 (PIP = 0.981) and TRIM59 (PIP = 0.936) among the top-ranked candidates. AlphaGenome highlighted regulatory perturbations at two chr3 variants. Western blot confirmed significant IFT80 downregulation and TRIM59 upregulation during osteoclast differentiation, consistent with computational predictions. Multi-layered genomic evidence provides convergent support for a putative causal association between latent epigenetic ageing and bone mineral density through monocyte-specific regulatory mechanisms, identifying the TRIM59–IFT80 locus and 45 candidate genes as priority targets for mechanistic validation.
Vitamin C may be important for maintaining skeletal muscle health and preventing sarcopenia, but most previous epidemiological studies have investigated dietary intakes rather than vitamin C status. To address this gap, this study investigated cross-sectional associations between both plasma and dietary vitamin C and muscle strength and physical performance. This study analysed data from over 5000 participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort (aged 48–92 years). Multivariable linear regression models, adjusted for lifestyle, biological, medical, and dietary covariates, were used to investigate associations between dietary (categorised as quintiles, Qs) and plasma vitamin C (low < 25μmol/L, suboptimal 25 to < 50μmol/L, optimal ≥ 50μmol/L), and handgrip strength (adjusted for height: HGSht), gait speed, and 5-chair-stand time. Least square means for outcome measures were calculated from regression models. Women with optimal versus low plasma vitamin C had higher HGSht (+ 0.54 kg/m2, p = 0.009), and faster gait speed and chair-stand time (+ 0.11m/s, p < 0.001; − 1.03s, p = 0.028, respectively). Men with optimal versus low plasma vitamin C had faster gait speed and chair-stand time (+ 0.05m/s, p = 0.01; − 0.71s, p = 0.026, respectively). Compared with Q1 of dietary intake, women in Q2 and Q5 had faster gait speed (+ 0.04m/s, p < 0.01 for both); women in Q4 and Q5 had faster chair-stand times (− 0.67s, p = 0.002; − 0.57s, p = 0.013, respectively). No associations were found for dietary vitamin C in men. These findings suggest that maintaining optimal plasma vitamin C status could be important for maintaining physical function. Longitudinal and intervention studies are needed to support our findings.
Bone mechanical competence depends not only on bone mass but also on the anisotropic orientation of the collagen/biological apatite (BAp) composite, yet its relationship to the local mechanical environment in human vertebrae remains unclear. Here, we examined whether region-specific BAp c-axis orientation corresponds to predominant principal stress direction estimated by µCT-based finite element analysis. The anterior region showed predominantly uniaxial alignment along the craniocaudal axis, corresponding to a predominant principal stress direction oriented primarily along the craniocaudal axis. In contrast, the cranial and caudal subchondral regions exhibited a two-dimensional in-plane orientation pattern corresponding to predominant principal stress directions within the anteroposterior–mediolateral plane, consistent with load transfer through the intervertebral disc, which imposes transverse in-plane loading on the endplate region. At the corticotrabecular junction, the preferred BAp orientation changed markedly within a spatial range of 100 μm or less. Overall, these findings demonstrate region-specific stress–orientation correspondence in human vertebrae and support crystallographic orientation as a quantitative bone-quality indicator of vertebral mechanical adaptation.
Systemic sclerosis (SSc) is associated with increased bone fragility, yet early, compartment-specific alterations and their osteoimmunological correlates remain incompletely characterized. This study aimed to assess bone status in SSc using dual X-ray absorptiometry (DXA) complemented by peripheral quantitative computed tomography (pQCT), and to evaluate their associations with a targeted osteoimmunological biomarker panel and clinical risk scores. This prospective cross-sectional study included 40 women with SSc (disease duration ≤ 7 years from diagnosis) and 45 non-immune female controls, frequency-matched by age. Bone status was assessed by DXA (lumbar spine, femoral neck) and distal radius pQCT. Serum levels of routine bone and mineral metabolism markers, alongside a targeted panel of osteoimmunological mediators (OPG, OPN, PDGF-BB, ACP5, RANKL, TNF-α, IL-6, IL-1β, DKK-1) using multiplex immunoassay were measured. FRAX scores were calculated to contextualize clinical fracture risk. With broadly comparable DXA-defined bone status, pQCT revealed significantly lower trabecular volumetric bone mineral density (vBMD) in SSc, while total and cortical+subcortical vBMD were comparable. Routine biochemical markers showed substantial overlap between groups, whereas SSc patients exhibited a distinct osteoimmune profile with significantly elevated OPG, ACP5, RANKL, PDGF-BB, IL-6, IL-1β, DKK-1, and RANKL/OPG after FDR correction. Exploratory biomarker–bone associations did not remain significant after correction for multiple testing. In women with relatively early SSc, pQCT identified compartment-specific differences, particularly within the trabecular compartment, despite comparable DXA-defined bone status. A distinct osteoimmunological biomarker profile was also observed in SSc, providing complementary information on disease-related skeletal alterations, while specific biomarker–bone associations require further confirmation.
Methylmalonic acid (MMA) is a functional marker of vitamin B12 insufficiency and an emerging metabolic factor associated with skeletal aging and osteoporosis. This review synthesizes epidemiological, experimental, and mechanistic evidence linking the vitamin B12–MMA axis to impaired bone homeostasis. Population studies associate elevated circulating MMA with lower bone mineral density, higher odds of osteoporosis, and lower knee extensor strength, while disturbed vitamin B12 metabolism has also been linked to altered bone turnover. Experimental MMA exposure and models of methylmalonyl-CoA mutase (MMUT) deficiency reveal context-dependent abnormalities in mitochondrial respiration, energy metabolism, redox balance, and quality control. These findings provide a rationale for investigating skeletal effects, but the broader consequences of vitamin B12 deficiency and inherited metabolic defects should be distinguished from direct MMA actions in bone cells. Concurrent homocysteine accumulation and reduced S-adenosylmethionine availability may further impair collagen cross-linking, epigenetic regulation, and skeletal remodeling. These pathways support a metabolic–mitochondrial framework in which functional vitamin B12 deficiency contributes to bone loss through coordinated effects on bioenergetics, redox balance, cell fate, and extracellular matrix quality. MMA may therefore complement vitamin B12, homocysteine, renal function, and conventional bone markers in the assessment of skeletal metabolic risk. Prospective human studies, bone-specific mechanistic experiments, and intervention trials are needed to establish causality, clinically useful thresholds, and the skeletal benefits of correcting vitamin B12 deficiency or targeting mitochondrial dysfunction.
