PPARγ deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage
Open accessAbstract
OBJECTIVES: We have previously shown that peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor, is essential for the normal growth and development of cartilage. In the present study, we created inducible cartilage-specific PPARγ knockout (KO) mice and subjected these mice to the destabilisation of medial meniscus (DMM) model of osteoarthritis (OA) to elucidate the specific in vivo role of PPARγ in OA pathophysiology. We further investigated the downstream PPARγ signalling pathway responsible for maintaining cartilage homeostasis. METHODS: Inducible cartilage-specific PPARγ KO mice were generated and subjected to DMM model of OA. We also created inducible cartilage-specific PPARγ/mammalian target for rapamycin (mTOR) double KO mice to dissect the PPARγ signalling pathway in OA. RESULTS: Compared with control mice, PPARγ KO mice exhibit accelerated OA phenotype with increased cartilage degradation, chondrocyte apoptosis, and the overproduction of OA inflammatory/catabolic factors associated with the increased expression of mTOR and the suppression of key autophagy markers. In vitro rescue experiments using PPARγ expression vector reduced mTOR expression, increased expression of autophagy markers and reduced the expression of OA inflammatory/catabolic factors, thus reversing the phenotype of PPARγ KO mice chondrocytes. To dissect the in vivo role of mTOR pathway in PPARγ signalling, we created and subjected PPARγ-mTOR double KO mice to the OA model to see if the genetic deletion of mTOR in PPARγ KO mice (double KO) can rescue the accelerated OA phenotype observed in PPARγ KO mice. Indeed, PPARγ-mTOR double KO mice exhibit significant protection/reversal from OA phenotype. SIGNIFICANCE: PPARγ maintains articular cartilage homeostasis, in part, by regulating mTOR pathway.
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PPARγ has a protective role in articular cartilage.
“it has been demonstrated that PPARγ has a protective role in articular cartilage.”
From Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy (2019) · cites this paper as [57]
Cartilage-specific PPARγ deficient mice showed increased apoptosis, increased production of inflammatory and catabolic factors, decreased expression of anabolic factors, and accelerated OA.
“Cartilage-specific PPARγ deficient mice showed increased apoptosis as well as production of inflammatory and catabolic factors, and a decreased expression of anabolic factors, overall resulting in accelerated OA [56,57].”
From Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy (2019) · cites this paper as [57]
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- Authors
- Vasheghani, F., Zhang, Y., Li, Y.-H., Blati, M., Fahmi, H., Lussier, B., Roughley, P., Lagares, D., Endisha, H., Saffar, B., Lajeunesse, D., Marshall, W. K., Rampersaud, Y. R., Mahomed, N. N., Gandhi, R., Pelletier, J.-P., Martel-Pelletier, J., & Kapoor, M.
- Affiliations
- Université de Montréal (CA)
- University Health Network (CA)
- McGill University (CA)
- Harvard University (US)
- Toronto Western Hospital (CA)
- Corresponding author
- Kapoor, Mohit
- ORCID
- Venue
- Annals of the Rheumatic Diseases
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 74
- Issue
- 3
- Pages
- 569-578
- ISSN
- 0003-4967 (ISSN-L)
- PMC
- PMC4345902
- OpenAlex
- W2109777848
- Cited by
- 221
- References
- 38
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 15 · 2023: 21 · 2022: 21 · 2021: 19 · 2020: 18 · 2019: 27 · 2018: 25 · 2017: 24 · 2016: 12 · 2015: 12
- FWCI
- 20.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Annals of the Rheumatic Diseases (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Arthritis Society
- Canadian Institutes of Health Research (106567_1, 126016_1)
- Medical Research Council (MR/K013076/1)
- Canadian Arthritis Network
- Topics
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- PPARγ, osteoarthritis, mTOR signaling, articular cartilage, cartilage homeostasis, chondrocyte apoptosis, cartilage degeneration, autophagy, PPARγ knockout mice
- MeSH terms
- Animals, Cartilage, Articular, Disease Models, Animal, Menisci, Tibial, Signal Transduction, Mice, Knockout, Osteoarthritis, Knee, PPAR gamma, Mice, TOR Serine-Threonine Kinases
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