SOCS2 deficiency drives sex-specific remodeling of mineralized tissues

Abstract

Sex-specific differences in bone development and remodeling are increasingly recognized as critical determinants in skeletal biology. We investigated the impact of SOCS2 deficiency on craniofacial and long bone structures in female and male mice. C57BL/6 wild-type (WT) and SOCS2 knockout (SOCS2−/−) mice underwent orthodontic tooth movement (OTM) on the right side, while the contralateral side served as control. Maxillae, dental roots, femur, adipose tissue, and serum were collected for histomorphometry, micro-computed tomography (microCT), biomechanical testing, adiposity index assessment, qPCR, Western blot, and ELISA. SOCS2−/−males exhibited greater alveolar bone loss and increased OTM than SOCS2−/−females. Whereas SOCS2−/−females showed reduced OTM compared with WT females. MicroCT revealed higher maxillary bone mineral density (BMD) in SOCS2−/−females, but lower BMD, bone volume/total volume, and trabecular thickness, with increased trabecular separation, in SOCS2−/−males. These phenotypes were associated with increased Howship's lacunae and c-Jun N-terminal kinase activity in SOCS2−/−males, sex-divergent Pparγ, Il6, and Runx2 expression, and unchanged Rankl/Opg ratio in maxillary bone. Femoral evaluations showed sex-specific changes in growth, bone structure, and mechanical strength. Root analyses revealed compromised architecture in SOCS2−/−males and increased odontoclast activity in both sexes. SOCS2−/−males displayed increased serum testosterone and adiposity, despite reduced adipocyte area, whereas SOCS2−/−females exhibited higher prolactin levels and enlarged adipocytes. SOCS2 influences skeletal remodeling in a sex-dependent manner, with underlying mechanisms involving metabolic and hormonal alterations, as well as local imbalances in the regulation of osteoblast and osteoclast activity.