PPAR-γ激活通过Nrf2/NLRP3和PGC-1α/Δψ m途径抑制骨关节炎的热凋亡

IF 3.5 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL PPAR Research Pub Date : 2023-01-01 DOI:10.1155/2023/2523536
Zhencheng Feng, Qiuxiang Huang, Xingliang Zhang, Pengfei Xu, Siming Li, Dongli Ma, Qingqi Meng
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引用次数: 6

摘要

骨关节炎(OA)是一种常见的退行性关节疾病,在老龄化和肥胖人群中发病率逐渐增加。新出现的证据表明,焦亡与OA的病因有关,它可能被认为是OA的治疗靶点。我们之前报道过另一种疾病,过氧化物酶体增殖物激活受体γ (PPAR-γ)激活通过抑制核苷酸结合和寡聚化结构域样受体蛋白(NLRP) 3炎性体发挥抗炎作用。然而,PPAR-γ与nlrp3介导的OA软骨焦亡之间的关系及其潜在机制尚不清楚。在本研究中,我们发现OA患者膝关节严重股骨外侧髁软骨磨损区nlrp3介导的焦下垂水平明显高于轻度股骨外侧髁软骨磨损区。此外,在脂多糖(LPS)/三磷酸腺苷(ATP)诱导的原代软骨细胞和膝关节OA大鼠模型中,我们证明了吡格列酮(Piog)激活PPAR-γ可减轻LPS/ATP诱导的软骨细胞热凋亡和关节炎。这些作用可通过阻断核因子红细胞2相关因子(Nrf2)/NLRP3或PGC1-α/Δψ m信号通路部分抵消。同时抑制这两种信号通路可以完全取消Piog对OA和软骨细胞的保护作用。综上所述,Piog通过同时激活Nrf2/NLRP3和PGC-1α/Δψ m通路来保护OA软骨免受热致损伤,从而增强抗氧化和抗炎反应以及线粒体生物发生。因此,Piog在未来的临床治疗中可能是一种有前景的治疗人OA软骨损伤的药物。
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PPAR-γ Activation Alleviates Osteoarthritis through Both the Nrf2/NLRP3 and PGC-1α/Δψ m Pathways by Inhibiting Pyroptosis.

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/Δψ m 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 pyroptosis-induced damage by simultaneously activating both the Nrf2/NLRP3 and PGC-1α/Δψ m pathways, which enhances antioxidative and anti-inflammatory responses as well as mitochondrial biogenesis. Therefore, Piog may be a promising agent for human OA cartilage damage in future clinical treatments.

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来源期刊
PPAR Research
PPAR Research MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
6.20
自引率
3.40%
发文量
17
审稿时长
12 months
期刊介绍: PPAR Research is a peer-reviewed, Open Access journal that publishes original research and review articles on advances in basic research focusing on mechanisms involved in the activation of peroxisome proliferator-activated receptors (PPARs), as well as their role in the regulation of cellular differentiation, development, energy homeostasis and metabolic function. The journal also welcomes preclinical and clinical trials of drugs that can modulate PPAR activity, with a view to treating chronic diseases and disorders such as dyslipidemia, diabetes, adipocyte differentiation, inflammation, cancer, lung diseases, neurodegenerative disorders, and obesity.
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