Menopause-induced 17β-estradiol and progesterone loss increases senescence markers, matrix disassembly and degeneration in mouse cartilage.

Female individuals who are post-menopausal present with higher incidence of knee osteoarthritis (KOA) than male counterparts; however, the mechanisms underlying this disparity are unknown. The most commonly used preclinical models lack human-relevant menopausal phenotypes, which may contribute to our incomplete understanding of sex-specific differences in KOA pathogenesis. Here we chemically induced menopause in middle-aged (14-16 months) C57/BL6N female mice. When we mapped the trajectory of KOA over time, we found that menopause aggravated cartilage degeneration relative to non-menopause controls. Network medicine analyses revealed that loss of 17β-estradiol and progesterone with menopause enhanced susceptibility to senescence and extracellular matrix disassembly. In vivo, restoration of 17β-estradiol and progesterone in menopausal mice protected against cartilage degeneration compared to untreated menopausal controls. Accordingly, post-menopausal human chondrocytes displayed decreased markers of senescence and increased markers of chondrogenicity when cultured with 17β-estradiol and progesterone. These findings implicate menopause-associated senescence and extracellular matrix disassembly in the sex-specific pathogenesis of KOA.