PPAR-γ Activation Alleviates Osteoarthritis through Both the Nrf2/NLRP3 and PGC-1α/Δψm Pathways by Inhibiting Pyroptosis

作者：Zhencheng Feng, Qiuxiang Huang, Xingliang Zhang, Pengfei Xu, Siming Li, Dongli Ma, Qingqi Meng · 发表于：PPAR Research · 年份：2023 · DOI：10.1155/2023/2523536 · 被引用次数：44 · 研究领域：Inflammasome and immune disorders、Gout, Hyperuricemia, Uric Acid、Peroxisome Proliferator-Activated Receptors

Osteoarthritis (OA) is a common degenerative joint disease with a gradually increasing morbidity in the aging and obese population. Emerging evidence has implicated pyroptosis in the etiology of OA and it may be recognized as a therapeutic target in OA. We have previously reported regarding another disease that peroxisome proliferator-activated receptor gamma (PPAR-γ) activation exerts an anti-inflammatory effect by suppressing the nucleotide-binding and oligomerization domain-like receptor containing protein (NLRP) 3 inflammasome. However, the relationship between PPAR-γ and NLRP3-mediated pyroptosis in OA cartilage and its underlying mechanisms is fully unclear. In this study, we found that the level of NLRP3-mediated pyroptosis in severe lateral femoral condyle cartilage wear in the knee of an OA patient was significantly higher than that in the mild lateral femoral condyle cartilage wear areas. Moreover, in lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-induced primary chondrocytes and knee OA rat models, we demonstrated that activation of PPAR-γ by pioglitazone (Piog) attenuated LPS/ATP-induced chondrocyte pyroptosis and arthritis. These effects were partially counteracted by either blocking the nuclear factor erythroid-2-related factor (Nrf2)/NLRP3 or PGC1-α/Δψm signaling pathway. Simultaneous depression of these two signaling pathways can completely abrogate the protective effects of Piog on OA and chondrocytes. Taken together, Piog protects OA cartilage against...