Oxylipin-PPARγ-initiated adipocyte senescence propagates secondary senescence in the bone marrow

Xiaonan Liu, Yiru Gu, Surendra Kumar, Sahran Amin, Qiaoyue Guo, Jiekang Wang, Ching Lien Fang, Xu Cao, Mei Wan

Research output: Contribution to journalArticlepeer-review

Abstract

The chronic use of glucocorticoids decreases bone mass and quality and increases bone-marrow adiposity, but the underlying mechanisms remain unclear. Here, we show that bone-marrow adipocyte (BMAd) lineage cells in adult mice undergo rapid cellular senescence upon glucocorticoid treatment. The senescent BMAds acquire a senescence-associated secretory phenotype, which spreads senescence in bone and bone marrow. Mechanistically, glucocorticoids increase the synthesis of oxylipins, such as 15d-PGJ2, for peroxisome proliferator-activated receptor gamma (PPARγ) activation. PPARγ stimulates the expression of key senescence genes and also promotes oxylipin synthesis in BMAds, forming a positive feedback loop. Transplanting senescent BMAds into the bone marrow of healthy mice is sufficient to induce the secondary spread of senescent cells and bone-loss phenotypes, whereas transplanting BMAds harboring a p16INK4a deletion did not show such effects. Thus, glucocorticoid treatment induces a lipid metabolic circuit that robustly triggers the senescence of BMAd lineage cells that, in turn, act as the mediators of glucocorticoid-induced bone deterioration.

Original languageEnglish (US)
Pages (from-to)667-684.e6
JournalCell Metabolism
Volume35
Issue number4
DOIs
StatePublished - Apr 4 2023

Keywords

  • INK-family proteins
  • PPARγ
  • bone marrow adipocytes
  • bone marrow adiposity
  • cellular senescence
  • glucocorticoids
  • osteoporosis
  • oxylipins
  • prostaglandins
  • senescence-associated secretory phenotype

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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