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Updated: Aug 14, 2026
Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis
Published on: June 3, 2016
Oxylipin-PPARγ-initiated adipocyte senescence propagates secondary senescence in the bone marrow
Xiaonan Liu1, Yiru Gu1, Surendra Kumar1
1Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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.
Insights
Glucocorticoid use causes bone loss by triggering cellular senescence in bone marrow fat cells. These senescent cells spread, leading to decreased bone mass and quality.
Area of Science:
- Biomedical Science
- Cell Biology
- Endocrinology
Background:
- Chronic glucocorticoid use is linked to reduced bone mass and quality.
- Increased bone marrow adiposity is observed with glucocorticoid therapy.
- The cellular mechanisms driving glucocorticoid-induced bone deterioration are not fully understood.
Purpose of the Study:
- To elucidate the mechanisms by which glucocorticoids induce bone loss.
- To investigate the role of bone marrow adipocytes (BMAds) in glucocorticoid-induced bone deterioration.
- To identify the cellular and molecular pathways involved in glucocorticoid-induced bone loss.
Main Methods:
- Treatment of adult mice with glucocorticoids.
- Analysis of cellular senescence in bone marrow adipocyte lineage cells.
- Investigation of oxylipin synthesis and peroxisome proliferator-activated receptor gamma (PPARγ) activation.
- Transplantation studies using senescent BMAds and p16INK4a-deleted BMAds.
Main Results:
- Glucocorticoid treatment induces rapid cellular senescence in BMAd lineage cells.
- Senescent BMAds exhibit a senescence-associated secretory phenotype, promoting senescence spread.
- A positive feedback loop involving oxylipins and PPARγ activation drives senescence.
- Transplantation of senescent BMAds causes secondary senescence spread and bone loss phenotypes.
Conclusions:
- Glucocorticoid-induced bone deterioration is mediated by senescent bone marrow adipocytes.
- A lipid metabolic circuit involving oxylipins and PPARγ activation is crucial for this process.
- Targeting BMAd senescence may offer therapeutic strategies for glucocorticoid-induced bone loss.
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