Sirt1 deletion in hypertrophic chondrocytes differentially regulates skeletal growth and bone accrual in males and females mice.

INTRODUCTION: We investigated the role of SIRT1 in linear growth and bone structure, focusing on the response of the epiphyseal growth plate (EGP) to nutritional manipulation. METHODS: A ColX-Cre driver was used to target hypertrophic chondrocytes (HZ), and generate hypertrophic specific Sirt1 knockout (CKO) mice. RESULTS: We found that Sirt1 deletion in hypertrophic chondrocytes markedly impaired growth in males, with a 33% reduction in body weight and 10-11% shorter long bones and EGP height (P<0.05). In females, effects were milder (12% reduction in weight, 5-7% shorter long bones; P<0.05 in both) but EGP height was reduced similarly to the males. These mice were next tested in a catch-up (CU) growth model involving food restriction followed by refeeding. Under CU conditions, male CKO mice showed an unexpected exaggerated response, surpassing the weight and bone length of normally fed CKO. DISCUSSION: We therefore conclude that targeted Sirt1 deletion in the hypertrophic zone revealed a strong sex-dependent effect on skeletal growth and bone quality. Both male and female CKO mice exhibited growth impairment under normal conditions compared to littermate control (CTL), however while male showed hyper-responsiveness to refeeding, females CKO showed only moderate alterations. This targeted approach uncovers sex-dependent role for SIRT1 in regulating growth and bone quality, moving beyond its generally understood functions in cartilage and bone development. The distinct responses to both basal conditions and nutritional stress between sexes represent a significant new finding, extending its known role beyond general cartilage and bone development.