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Cited by 137Telomeres, Telomerase, and SenescenceBone Metabolism and DiseasesAdipose Tissue and Metabolism

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

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Liu, Xiaonan, Gu, Yiru, Kumar, Surendra, Amin, Sahran, Guo, Qiaoyue, Wang, Jiekang, Fang, Ching-Lien, Cao, Xu +1 more·2023·Cell Metabolism
DOI 10.1016/j.cmet.2023.03.005PMC PMC10127143
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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.

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  • PPARγ is a key transcription factor mediating p16Ink4a gene activation and BMAd senescence.

    “Previous studies revealed that PPARγ is a key transcription factor mediating p16Ink4a gene activation53 and BMAd senescence47.”

    From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [47]

  • The majority of the elevated factors in this context differ from the SASP factors previously identified in glucocorticoid-induced senescent BMAds.

    “It is noteworthy that the majority of the elevated factors in this context differ from the SASP factors previously identified in glucocorticoid-induced senescent BMAds47.”

    From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [47]

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Cited by

Sorted by citations

Authors
Liu, X., Gu, Y., Kumar, S., Amin, S., Guo, Q., Wang, J., Fang, C.-L., Cao, X., & Wan, M.
Affiliations
Johns Hopkins University (US)
Corresponding author
Wan, Mei
ORCID
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2023-04
Volume
35
Issue
4
Pages
667-684.e6
ISSN
1550-4131 (ISSN-L)
DOI
10.1016/j.cmet.2023.03.005
PMC
PMC10127143
OpenAlex
W4362604553
Cited by
137
References
87
Citations by year
2026: 57 · 2025: 36 · 2024: 32 · 2023: 12
FWCI
24.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Irving Medical Center, Columbia University
  • National Institutes of Health (P01AG066603, R01AG068226, R01AG072090)
  • Buck Institute for Research on Aging
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
glucocorticoid-induced osteoporosis, bone marrow adipocytes, cellular senescence, senescence-associated secretory phenotype, oxylipins, 15-deoxy-delta12-prostaglandin J2, PPARγ, p16INK4a, lipid metabolism, positive feedback loop
MeSH terms
Animals, Bone Marrow, Bone Marrow Cells, Glucocorticoids, Cellular Senescence, Adipocytes, PPAR gamma, Mice, Oxylipins

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