PPARδ Agonist Protects Against Osteoarthritis by Activating AKT/mTOR Signaling Pathway-mediated Autophagy

Overview

Journal Front Pharmacol

Date 2024 Apr 5

PMID 38576477

Authors

Guantong Sun

Xiaodong Li

Pengcheng Liu

Yao Wang

Cheng Yang

Shuhong Zhang

Lei Wang

Xiaoqing Wang

Affiliations

Soon will be listed here.

Abstract

Osteoarthritis (OA) is the most prevalent degenerative joint disease, and PPARs are involved in its pathogenesis; however, the specific mechanisms by which changes in PPARδ impact the OA pathogenesis yet to be discovered. The purpose of this study was to ascertain how PPARδ affects the onset and development of OA. , we found that PPARδ activation ameliorated apoptosis and extracellular matrix (ECM) degradation in OA chondrocytes stimulated by IL-1β. In addition, PPARδ activation may modulate AKT/mTOR signaling to partially regulate chondrocyte autophagy and apoptosis. , injection of PPARδ agonist into the articular cavity improved ECM degradation, apoptosis and autophagy in rats OA models generated by destabilization medial meniscus (DMM), eventually delayed degeneration of articular cartilage. Thus, targeting PPARδ for OA treatment may be a possibility.

References

Poleni P, Bianchi A, Etienne S, Koufany M, Sebillaud S, Netter P . Agonists of peroxisome proliferators-activated receptors (PPAR) alpha, beta/delta or gamma reduce transforming growth factor (TGF)-beta-induced proteoglycans' production in chondrocytes. Osteoarthritis Cartilage. 2006; 15(5):493-505. DOI: 10.1016/j.joca.2006.10.009. View

Gross B, Pawlak M, Lefebvre P, Staels B . PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD. Nat Rev Endocrinol. 2016; 13(1):36-49. DOI: 10.1038/nrendo.2016.135. View

Li W, He P, Huang Y, Li Y, Lu J, Li M . Selective autophagy of intracellular organelles: recent research advances. Theranostics. 2021; 11(1):222-256. PMC: 7681076. DOI: 10.7150/thno.49860. View

Rahmati M, Nalesso G, Mobasheri A, Mozafari M . Aging and osteoarthritis: Central role of the extracellular matrix. Ageing Res Rev. 2017; 40:20-30. DOI: 10.1016/j.arr.2017.07.004. View

Mizushima N, Levine B, Cuervo A, Klionsky D . Autophagy fights disease through cellular self-digestion. Nature. 2008; 451(7182):1069-75. PMC: 2670399. DOI: 10.1038/nature06639. View

Mulcahy Levy J, Towers C, Thorburn A . Targeting autophagy in cancer. Nat Rev Cancer. 2017; 17(9):528-542. PMC: 5975367. DOI: 10.1038/nrc.2017.53. View

Vasheghani F, Zhang Y, Li Y, Blati M, Fahmi H, Lussier B . PPARγ deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage. Ann Rheum Dis. 2015; 74(3):569-78. PMC: 4345902. DOI: 10.1136/annrheumdis-2014-205743. View

Creamer P, Hochberg M . Osteoarthritis. Lancet. 1997; 350(9076):503-8. DOI: 10.1016/S0140-6736(97)07226-7. View

Glyn-Jones S, Palmer A, Agricola R, Price A, Vincent T, Weinans H . Osteoarthritis. Lancet. 2015; 386(9991):376-87. DOI: 10.1016/S0140-6736(14)60802-3. View

10.

Dewanjee S, Vallamkondu J, Kalra R, John A, Reddy P, Kandimalla R . Autophagy in the diabetic heart: A potential pharmacotherapeutic target in diabetic cardiomyopathy. Ageing Res Rev. 2021; 68:101338. DOI: 10.1016/j.arr.2021.101338. View

11.

Chen X, Gong W, Shao X, Shi T, Zhang L, Dong J . METTL3-mediated mA modification of ATG7 regulates autophagy-GATA4 axis to promote cellular senescence and osteoarthritis progression. Ann Rheum Dis. 2021; 81(1):87-99. DOI: 10.1136/annrheumdis-2021-221091. View

12.

Sciarretta S, Maejima Y, Zablocki D, Sadoshima J . The Role of Autophagy in the Heart. Annu Rev Physiol. 2017; 80:1-26. DOI: 10.1146/annurev-physiol-021317-121427. View

13.

Abramoff B, Caldera F . Osteoarthritis: Pathology, Diagnosis, and Treatment Options. Med Clin North Am. 2020; 104(2):293-311. DOI: 10.1016/j.mcna.2019.10.007. View

14.

Zhou Y, Chen X, Qu N, Zhang B, Xia C . Chondroprotection of PPARα activation by WY14643 via autophagy involving Akt and ERK in LPS-treated mouse chondrocytes and osteoarthritis model. J Cell Mol Med. 2019; 23(4):2782-2793. PMC: 6433667. DOI: 10.1111/jcmm.14184. View

15.

Liu Y, Luo S, Zhan Y, Wang J, Zhao R, Li Y . Increased Expression of PPAR-γ Modulates Monocytes Into a M2-Like Phenotype in SLE Patients: An Implicative Protective Mechanism and Potential Therapeutic Strategy of Systemic Lupus Erythematosus. Front Immunol. 2021; 11:579372. PMC: 7873911. DOI: 10.3389/fimmu.2020.579372. View

16.

Christofides A, Konstantinidou E, Jani C, Boussiotis V . The role of peroxisome proliferator-activated receptors (PPAR) in immune responses. Metabolism. 2020; 114:154338. PMC: 7736084. DOI: 10.1016/j.metabol.2020.154338. View

17.

Sakai S, Yamamoto T, Takabatake Y, Takahashi A, Namba-Hamano T, Minami S . Proximal Tubule Autophagy Differs in Type 1 and 2 Diabetes. J Am Soc Nephrol. 2019; 30(6):929-945. PMC: 6551771. DOI: 10.1681/ASN.2018100983. View

18.

Mirza A, Althagafi I, Shamshad H . Role of PPAR receptor in different diseases and their ligands: Physiological importance and clinical implications. Eur J Med Chem. 2019; 166:502-513. DOI: 10.1016/j.ejmech.2019.01.067. View

19.

Muller R . PPARβ/δ in human cancer. Biochimie. 2016; 136:90-99. DOI: 10.1016/j.biochi.2016.10.019. View

20.

Mizushima N, Komatsu M . Autophagy: renovation of cells and tissues. Cell. 2011; 147(4):728-41. DOI: 10.1016/j.cell.2011.10.026. View