Increased HIF-1α in Knee Osteoarthritis Aggravate Synovial Fibrosis via Fibroblast-Like Synoviocyte Pyroptosis
Increased HIF-1α in Knee Osteoarthritis Aggravate Synovial Fibrosis via Fibroblast-Like Synoviocyte Pyroptosis
复制标题
膝骨关节炎中 HIF-1α 的增加通过成纤维细胞样滑膜细胞焦亡加重滑膜纤维化
DOI：
10.1155/2019/6326517
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发表时间：
2019-01-01
影响因子：
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通讯作者：
Wang, Peimin
中科院分区：
文献类型：
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作者：
Zhang, Li;Huang, Zhengquan;Wang, Peimin
成纤维细胞样滑膜细胞（FLS）是膝骨关节炎（KOA）滑膜纤维化的主要效应细胞。我们的最新报告表明，NLRP 1和NLRP 3炎性体可能介导KOA中LPS/ATP诱导的FLS焦亡。本研究发现KOA模型大鼠滑膜组织中缺氧诱导因子-1 α（HIF-1α）水平升高，抑制HIF-1α的升高可改善大鼠滑膜纤维化。随后，我们建立了LPS/ATP诱导的FLS模型，模拟KOA的炎症环境。转染HIF-1α siRNA的FLS细胞死亡率降低，同时，细胞凋亡相关蛋白的相对表达也下调。此外，将用或不用siRNA GSDMD转染的FLS暴露于缺氧。GSDMD沉默可显著降低纤维化标志物转化生长因子-β（TGF-β）、前胶原-赖氨酸、2-酮戊二酸5-双加氧酶2（PLOD 2）、I型胶原α1链（COL 1A 1）和金属蛋白酶组织抑制剂1（TIMP 1）的基因和蛋白水平。总之，我们的研究结果表明，增加HIF-1α是高度参与KOA滑膜纤维化。此外，HIF-1α的升高可能通过FLS焦亡加重滑膜纤维化。
Fibroblast-like synoviocytes (FLSs) are the main effector cells of knee osteoarthritis (KOA) synovial fibrosis. Our last report showed that NLRP1 and NLRP3 inflammasomes may mediate LPS/ATP-induced FLSs pyroptosis in KOA. In the present study, we found an elevated hypoxia-inducible factor-1α (HIF-1α) level in the synovial tissue of KOA model rats, and inhibiting the increase of HIF-1α could improve synovial fibrosis in rats. Subsequently, we established LPS/ATP-induced model in FLSs mimicking the inflammatory environment of KOA. FLSs transfected with siRNA HIF-1α showed a reduced cell death; meanwhile, the relative expression of pyroptosis-related proteins was also downregulated. Additionally, FLSs transfected with or without siRNA GSDMD were exposed to hypoxia. GSDMD silencing can significantly reduce both gene and protein levels of fibrogenic markers transforming growth factor-β (TGF-β), procollagen-lysine, 2-oxoglutarate 5-dioxygenase2 (PLOD2), collagen type I α1 chain (COL1A1), and tissue inhibitor of metalloproteinases 1 (TIMP1). Taken together, our findings indicate that increased HIF-1α is highly involved in the KOA synovial fibrosis. Moreover, elevated HIF-1α may aggravate synovial fibrosis via FLS pyroptosis.