Rheumatoid arthritis (RA) is characterized by synovial inflammation, synoviocyte expansion and damage to cartilage and bone. We recently reported that peroxisome proliferator-activated receptor (PPAR)-γ inhibited the proliferation and activation of fibroblast-like synoviocytes (FLS), and was downregulated in RA synovial. In this study we investigated the role of PPAR-γ in RA and the underlying mechanisms. Adjuvant-induced arthritis (AIA) was induced in rats; from D15, AIA rats were orally administered pioglitazone (30 mg·kg⁻¹·d⁻¹) or rosiglitazone (4 mg·kg⁻¹·d⁻¹) for 14 days. Collagen-induced arthritis (CIA) was induced in wild-type and Ppar-γ^+/− mice. We showed that the expression of PPAR-γ was significantly reduced, whereas that of TNF-α was markedly increased in human RA FLS. In CIA mice, knockdown of PPAR-γ expression (Ppar-γ^+/−) aggravated the ankle inflammation. Similarly, T0070907 (a PPAR-γ antagonist) or si-PPAR-γ promoted the activation and inflammation of TNF-α-induced FLS in vitro. On the contrary, administration of PPAR-γ agonist pioglitazone or rosiglitazone, or injection of ad-Ppar-γ into the ankle of AIA rat in vivo induced overexpression of PPAR-γ, reduced the paw swelling and inflammation, and downregulated activation and inflammation of FLS in RA. Interesting, injection of ad-Ppar-γ into the ankle also reversed the ankle inflammation in Ppar-γ^+/− CIA mice. We conducted RNA-sequencing and KEGG pathway analysis, and revealed that PPAR-γ overexpression was closely related to p53 signaling pathway in TNF-α-induced FLS. Co-IP study confirmed that p53 protein was bound to PPAR-γ in RA FLS. Taken together, PPAR-γ alleviates the inflammatory response of TNF-α-induced FLS by binding p53 in RA.

类风湿性关节炎 (RA) 的特征在于滑膜炎症、滑膜细胞扩张以及软骨和骨骼损伤。我们最近报道过氧化物酶体增殖物激活受体 (PPAR)-γ 抑制成纤维细胞样滑膜细胞 (FLS) 的增殖和活化，并在 RA 滑膜中下调。在本研究中，我们研究了 PPAR-γ 在 RA 中的作用及其潜在机制。在大鼠中诱发佐剂性关节炎 (AIA)；从D15开始，给AIA大鼠口服吡格列酮（30 mg·kg ^-1 ·d ^-1）或罗格列酮（4 mg·kg ^-1 ·d ^-1）14天。胶原蛋白诱导的关节炎 (CIA) 在野生型和Ppar-γ ^{+/-中被诱导}老鼠。我们发现 PPAR-γ 的表达显着降低，而 TNF-α 的表达在人 RA FLS 中显着增加。在 CIA 小鼠中，PPAR-γ 表达 ( Ppar-γ ^+/- ) 的敲低加剧了脚踝炎症。同样，T0070907（一种 PPAR-γ 拮抗剂）或si-PPAR-γ在体外促进 TNF-α 诱导的 FLS 的激活和炎症。相反，在 AIA 大鼠体内给予 PPAR-γ 激动剂吡格列酮或罗格列酮，或注射ad-Ppar-γ可诱导 PPAR-γ 过表达，减轻足部肿胀和炎症，下调RA 中的 FLS。有趣的是，将ad-Ppar-γ注射到脚踝中也逆转了脚踝炎症Ppar-γ ^+/- CIA 小鼠。我们进行了 RNA 测序和 KEGG 通路分析，揭示了 PPAR-γ 过表达与 TNF-α 诱导的 FLS 中的 p53 信号通路密切相关。Co-IP 研究证实 p53 蛋白与 RA FLS 中的 PPAR-γ 结合。总之，PPAR-γ 通过结合 RA 中的 p53 减轻 TNF-α 诱导的 FLS 的炎症反应。