Samvelyan, J. | bioRxiv Science

bioRxiv2025

Tartrate-resistant acid phosphatase (TRAP/ACP5) sex-specifically regulates bone maintenance in old mice, but the anabolic effects of mechanical loading is regulated in a sex-independent way

Tartrate-resistant acid phosphatase (TRAP/ACP5), primarily known as an osteoclast marker, has emerged as a critical regulator of skeletal integrity, regulating sex-specific bone growth, and bones response to mechanical load in young adult male mice. In this study, we investigated the sex-specific roles of TRAP in bone structure and response to mechanical stimuli in old (19-month-old) wild-type (WT) and TRAP-deficient (TRAP-/-) mice using micro-computed tomography, serum bone turnover markers, in vivo axial mechanical loading, and in vitro mechanotransduction assays. Our findings revealed that TRAP-/- mice of both sexes maintained shorter tibiae than WT mice independent of sex. Notably, male, but not female, TRAP-/- mice have increased trabecular bone volume fraction and cortical bone area compared to WT, indicative of disrupted bone remodelling processes in male mice. Interestingly, TRAP-deficiency substantially impaired the anabolic bone response to mechanical loading, affecting both trabecular and cortical compartments in both sexes, indicating that when challenged, TRAP is important for bone formation also in female mice. Mechanical stimulation in vitro of hematopoietic progenitor cells from WT and TRAP-/- mice revealed that the increased ATP-release in response to mechanical stimulation was only disrupted in male mice, while mechanically induced increase in osteoclast formation was inhibited in TRAP-/- mice of both sexes. These results highlight the importance of TRAP in maintaining trabecular architecture and cortical bone in male mice and underscore its critical function in mediating adaptive responses to mechanical loading of both sexes, during aging. Future investigations should focus on elucidation of TRAP-dependent pathways as potential therapeutic targets to counteract age-related deficits in bone adaptation and remodelling.

developmental biology↗

bioRxiv2021

Ciliary IFT88 safeguards coordinated epiphyseal vascularisation, resorption and ossification from disruptive physiological mechanical forces

In the musculoskeletal system, appropriate cell and tissue responses to mechanical force delineate morphogenesis and ensure lifelong health. Despite this, how mechanical cues are integrated into biological programmes remains unclear. Primary cilia are microtubule-based organelles that tune a range of cell activities, including signalling cascades activated or modulated, by extracellular biophysical cues. Here, we demonstrate that the inducible, cartilage-specific deletion of Intraflagellar transport protein 88 (IFT88), which reduces ciliation in the adolescent mouse growth plate (GP), uncouples chondrocyte differentiation from cartilage resorption and mineralisation in a mechano-dependent manner. Targeting IFT88, inhibits hypertrophic chondrocyte VEGF expression, vascular recruitment, osteoclastic activity and the replacement of cartilage with bone. These effects are largely restricted to peripheral tibial regions beneath the load-bearing compartments of the knee. Increases in physiological loading, in control mice, also impairs ossification in the peripheral GP, mimicking the effects of IFT88 deletion. Strikingly, limb immobilisation rescues disrupted VEGF and restores epiphyseal dynamics in Ift88cKO mice. These data indicate, that during this pivotal phase in adolescent skeletal maturation that defines the cessation of growth, ciliary IFT88 protects the coordinated ossification of the growth plate from an otherwise disruptive heterogeneity of physiological mechanical forces.

physiology↗