Preprint: Mitochondrial dysfunction contributes to accelerated musculoskeletal ageing in an FGFR3 hypochondroplasia mouse model

A bioRxiv preprint describes the musculoskeletal phenotype of a mouse model carrying a variant in the fibroblast growth factor receptor 3 gene (FGFR3) associated with hypochondroplasia (HCH) — a mild skeletal dysplasia in humans caused by activating FGFR3 variants. The study characterises progressive bone fragility, accelerated age-related changes in articular cartilage and subchondral bone, and reduced muscle fibre size and strength in Hch mice compared with wild-type controls.

Proteomics analyses of cortical bone revealed that the Hch model follows a distinct ageing trajectory from controls, and the authors identify mitochondrial dysfunction as a key molecular feature of this divergence. Disrupted mitochondrial function in musculoskeletal tissues may contribute to the accelerated tissue degeneration observed in the model, though the causal chain between FGFR3 activation, mitochondrial biology, and skeletal ageing phenotypes requires further characterisation.

Hypochondroplasia is a relatively under-studied skeletal dysplasia compared with achondroplasia, which is caused by a more severe activating variant in the same FGFR3 gene. The mechanistic findings reported here may inform understanding of premature musculoskeletal ageing more broadly and raise questions about whether mitochondrial pathways represent therapeutic targets in FGFR3-related skeletal conditions.

This is a preprint and has not undergone peer review.