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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年1月16日

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  • Gabrielle Gilmer,
  • Hirotaka Iijima,
  • Zachary R. Hettinger,
  • Natalie Jackson,
  • Juliana Bergmann,
  • Allison C. Bean,
  • Nafiseh Shahshahan,
  • Ekaterina Creed,
  • Rylee Kopchak,
  • Kai Wang,
  • Hannah Houston,
  • Jonathan M. Franks,
  • Michael J. Calderon,
  • Claudette St Croix,
  • Rebecca C. Thurston,
  • Christopher H. Evans,
  • Fabrisia Ambrosio

摘要

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.