Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Erlangen, Germany.
Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
Ann Rheum Dis. 2020 Sep;79(9):1227-1233. doi: 10.1136/annrheumdis-2020-216963. Epub 2020 Jun 1.
Coactivators are a heterogeneous family of transcriptional regulators that are essential for modulation of transcriptional outcomes and fine-tune numerous cellular processes. The aim of the present study was to evaluate the role of the coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in the pathogenesis of systemic sclerosis (SSc).
Expression of PGC-1α was analysed by real-time PCR, western blot and immunofluorescence. Modulation of autophagy was analysed by reporter studies by expression of autophagy-related genes. The effects of PGC-1α knockdown on collagen production and myofibroblast differentiation were analysed in cultured human fibroblasts and in two mouse models with fibroblast-specific knockout of PGC-1α.
The expression of PGC-1α was induced in dermal fibroblasts of patients with SSc and experimental murine fibrosis. Transforming growth factor beta (TGFβ), hypoxia and epigenetic mechanisms regulate the expression of PGC-1α in fibroblasts. Knockdown of PGC-1α prevented the activation of autophagy by TGFβ and this translated into reduced fibroblast-to-myofibroblast differentiation and collagen release. Knockout of PGC-1α in fibroblasts prevented skin fibrosis induced by bleomycin and by overexpression of a constitutively active TGFβ receptor type I. Moreover, pharmacological inhibition of PGC-1α by SR18292 induced regression of pre-established, bleomycin-induced skin fibrosis.
PGC-1α is upregulated in SSc and promotes autophagy to foster TGFβ-induced fibroblast activation. Targeting of PGC-1α prevents aberrant autophagy, inhibits fibroblast activation and tissue fibrosis and may over therapeutic potential.
共激活因子是转录调节因子的一个异质家族，对于调节转录结果和微调许多细胞过程至关重要。本研究旨在评估共激活因子过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）在系统性硬化症（SSc）发病机制中的作用。
通过实时 PCR、western blot 和免疫荧光分析 PGC-1α 的表达。通过表达自噬相关基因的报告研究分析自噬的调节。通过在培养的人成纤维细胞中和具有成纤维细胞特异性 PGC-1α 敲除的两种小鼠模型中分析 PGC-1α 敲低对胶原蛋白产生和肌成纤维细胞分化的影响。
SSc 患者和实验性小鼠纤维化的皮肤成纤维细胞中诱导了 PGC-1α 的表达。转化生长因子β（TGFβ）、缺氧和表观遗传机制调节成纤维细胞中 PGC-1α 的表达。PGC-1α 的敲低可防止 TGFβ激活自噬，从而减少成纤维细胞向肌成纤维细胞的分化和胶原蛋白释放。成纤维细胞中 PGC-1α 的敲除可预防博莱霉素诱导的皮肤纤维化和组成型激活 TGFβ受体 I 的过表达引起的皮肤纤维化。此外，PGC-1α 的药理学抑制物 SR18292 诱导了预先建立的博莱霉素诱导的皮肤纤维化的消退。
PGC-1α 在 SSc 中上调，并促进自噬以促进 TGFβ诱导的成纤维细胞激活。靶向 PGC-1α 可防止异常自噬、抑制成纤维细胞激活和组织纤维化，并可能具有治疗潜力。
