<b>INFLUENCES ON BONE MECHANOSENSITIVITY: </b><b>MECHANICAL LOAD HISTORY AND ALTERATION IN THE GUT-BONE AXIS</b>

<p dir="ltr">Bone, a part of the musculoskeletal system, senses and adapts to mechanical stimuli, a process essential for maintaining functional bone mass and tissue integrity. Disruption of this process can lead to bone metabolic disorders such as osteoporosis. However, the mechanisms by which bone responds to mechanical signals under varying physical and systemic conditions remain incompletely understood. These studies examine how mechanical and systemic perturbations influence bone metabolism. We first developed and validated two in vivo tibial loading models that generate distinct strain distribution patterns and assessed their effects on spatial gene expression. By integrating strain mapping with spatial transcriptomics, we demonstrated that bone responds differently to non-physiological strain patterns, an effect predominant in tensile strain mode, revealing relevant genes and biological processes regulating this effect. We then investigated how functional differences in sprawling locomotion affect bone responsiveness, using green iguana hindlimb model. Despite both the tibia and fibula playing distinct mechanical roles, the tibia showed greater mechanosensitivity and a stronger correlation with strain magnitude, suggesting functional history shapes adaptability. Lastly, we evaluated the effects of gut microbiome disruption and exercise on bone health. Results showed sex-dependent outcomes that female mice were more susceptible to antibiotic-induced bone loss and showed limited recovery through exercise, while males experienced improved mineralization. Together, these findings highlight the complex interactions between mechanical loading, systemic health, and skeletal adaptation. This work advances our understanding of bone mechanobiology and offers insights for developing strategies to treat bone metabolic diseases.</p>