PDF(Pubmed)
Abstract：
UNASSIGNED: Rheumatoid arthritis (RA) is a systemic autoimmune disease. Its pathogenesis has not yet been clarified, so it is urgent to explore therapeutic targets. Here, we clarified the role of HDAC6 in the mechanism of action of RA through mediating chaperone-mediated autophagy (CMA) to provide a clinical treatment of RA.
UNASSIGNED: We used rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and collagen-induced arthritis mice (CIA mice) as models of RA and pharmacological inhibitors as well as genetic interference with adeno-associated viruses to reduce the expression of HDAC6. We explored the influence of CAY10603 on RA-FLS proliferation and inflammation, as well as the expression of proteins related to the CMA signaling pathway. CIA model was constructed using DBA/1J mice. Arthritis symptoms in CIA mice were evaluated, and the expression and localization of CMA-related proteins in mouse ankle joints were examined.
UNASSIGNED: CAY10603 inhibited proliferation as well as the level of the molecular chaperone autophagy in RA-FLS. HDAC6 shRNA significantly reduced the clinical signs of arthritis in CIA mice, as did the expression of HDAC6 in the serum and ankle synovial tissues of CIA mice. Finally, it significantly inhibited the level of Hsc70 and LAMP-2A, which are involved in the CMA signaling pathway, in ankle joint tissues.
UNASSIGNED: Downregulation of HDAC6 may inhibit CMA and thereby ameliorate RA.
UNASSIGNED: We used rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and collagen-induced arthritis mice (CIA mice) as models of RA and pharmacological inhibitors as well as genetic interference with adeno-associated viruses to reduce the expression of HDAC6. We explored the influence of CAY10603 on RA-FLS proliferation and inflammation, as well as the expression of proteins related to the CMA signaling pathway. CIA model was constructed using DBA/1J mice. Arthritis symptoms in CIA mice were evaluated, and the expression and localization of CMA-related proteins in mouse ankle joints were examined.
UNASSIGNED: CAY10603 inhibited proliferation as well as the level of the molecular chaperone autophagy in RA-FLS. HDAC6 shRNA significantly reduced the clinical signs of arthritis in CIA mice, as did the expression of HDAC6 in the serum and ankle synovial tissues of CIA mice. Finally, it significantly inhibited the level of Hsc70 and LAMP-2A, which are involved in the CMA signaling pathway, in ankle joint tissues.
UNASSIGNED: Downregulation of HDAC6 may inhibit CMA and thereby ameliorate RA.
摘要：
■类风湿性关节炎(RA)是一种全身性自身免疫性疾病。其发病机制尚未明确,因此迫切需要探索治疗靶点。这里,我们阐明HDAC6通过介导分子伴侣介导的自噬(CMA)在RA作用机制中的作用,为RA的临床治疗提供依据.
■我们使用类风湿性关节炎成纤维细胞样滑膜细胞（RA-FLS）和胶原诱导的关节炎小鼠（CIA小鼠）作为RA和药理学抑制剂的模型，并使用腺相关病毒的遗传干扰来减少HDAC6的表达。我们探讨了CAY10603对RA-FLS增殖和炎症的影响，以及CMA信号通路相关蛋白的表达。使用DBA/1J小鼠构建CIA模型。评估CIA小鼠的关节炎症状，并检测了CMA相关蛋白在小鼠踝关节中的表达和定位。
■CAY10603抑制RA-FLS细胞增殖以及分子伴侣自噬水平。HDAC6shRNA显着降低CIA小鼠关节炎的临床体征，HDAC6在CIA小鼠血清和踝关节滑膜组织中的表达也是如此。最后,它显著抑制Hsc70和LAMP-2A的水平，参与CMA信号通路，踝关节组织。
■下调HDAC6可抑制CMA，从而改善RA。
■我们使用类风湿性关节炎成纤维细胞样滑膜细胞（RA-FLS）和胶原诱导的关节炎小鼠（CIA小鼠）作为RA和药理学抑制剂的模型，并使用腺相关病毒的遗传干扰来减少HDAC6的表达。我们探讨了CAY10603对RA-FLS增殖和炎症的影响，以及CMA信号通路相关蛋白的表达。使用DBA/1J小鼠构建CIA模型。评估CIA小鼠的关节炎症状，并检测了CMA相关蛋白在小鼠踝关节中的表达和定位。
■CAY10603抑制RA-FLS细胞增殖以及分子伴侣自噬水平。HDAC6shRNA显着降低CIA小鼠关节炎的临床体征，HDAC6在CIA小鼠血清和踝关节滑膜组织中的表达也是如此。最后,它显著抑制Hsc70和LAMP-2A的水平，参与CMA信号通路，踝关节组织。
■下调HDAC6可抑制CMA，从而改善RA。
