High-fat diet induces endoplasmic reticulum stress to promote chondrocyte apoptosis in mouse knee joints

Li Tan, Lindsey Harper, Margaret A. McNulty, Cathy S. Carlson, Raghunatha R. Yammani

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Mice fed a high-fat diet (HFD) become obese and develop osteoarthritis (OA)-like lesions, including chondrocyte apoptosis, in the knee joints. However, the mechanism by which HFD/obesity induces chondrocyte apoptosis is not clearly understood. In the present study, male mice were fed a low-fat diet (LFD, 10% kcal), HFD (45% kcal), or a HFD administered with 0.5 g/kg bodyweight of 4-phenyl butyric acid (PBA, a small chaperone known to ease endoplasmic reticulum [ER] stress), via the drinking water. At the end of the 18-week study, stifle (knee) joints from all animals were collected, fixed, paraffin embedded, and sectioned. Immunostaining of joints from the HFD group showed increased expression of ER stress and apoptotic markers and increased expression of nuclear protein 1 and tribbles related protein-3 compared to the LFD group. Mice on HFD also showed higher percentage of chondrocyte death, lower chondrocyte numbers per cartilage area, and thickening of subchondral bone. Administration of PBA alleviated all of the HFD-induced symptoms. Our study demonstrated that HFD induces ER stress to promote chondrocyte death and subchondral bone thickening, which could be relieved by alleviating ER stress via PBA administration, suggesting that ER stress could play an important role in obesity-linked OA and could be targeted for OA therapeutics.

Original languageEnglish (US)
Pages (from-to)5818-5826
Number of pages9
JournalFASEB Journal
Issue number4
StatePublished - Apr 1 2020

Bibliographical note

Funding Information:
This work was supported by the National Institute of Arthritis, Musculoskeletal and Skin Diseases (R01 AR066105) to RRY.

Publisher Copyright:
© 2020 Federation of American Societies for Experimental Biology


  • PBA
  • apoptosis
  • endoplasmic reticulum stress
  • obesity
  • osteoarthritis

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural


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