Department of Sports Medicine, Peking University Shenzhen Hospital, Shenzhen, China.
Physiol Res. 2020 Jul 16;69(3):467-479. doi: 10.33549/physiolres.934295. Epub 2020 May 29.
Circulating miRNAs have been proposed as the effective diagnostic biomarkers for muscular fibrosis-associated diseases. However, circulating biomarkers for early diagnosis of contracture muscles are limited in gluteal muscle contracture (GMC) patients. Here we sought to explore the abnormally expressed miRNAs in plasma and contraction bands of GMC patients. The results showed miR-29a-3p expression in plasma and contraction bands tissue was significantly reduced in GMC patients compared with normal control. Cell viability and levels of proliferation-associated protein cyclin D1 and cyclin-dependent-kinase 2 (CDK2) were powerfully inhibited by miR-29a mimics and enhanced by miR-29a inhibitor compared with negative control. Furthermore, miR-29a mimics effectively impeded, while miR-29a inhibitor enhanced the expression of collagen I and collagen III, followed by the secretion of transforming growth factor beta1 (TGF-beta1), TGF-beta3 and connective tissue growth factor (CTGF) in primary human contraction bands (CB) fibroblasts. The miR-29a-3p negatively regulated the expression of TGF-beta1 through binding to the 3´ UTR region of SERPINH1 (encoding heat shock protein HSP47), but had no effect on Smad2 activity. The miR-29a-3p was inversely correlated with HSP47 in contraction bands tissue from GMC patients. Collectively, miR-29a was notably depressed and regulated cell viability and fibrosis by directly targeting HSP47 in GMC, which suggest that circulating miR-29a might be a potential biomarker for early diagnosis and provides a novel therapeutic target for GMC.
循环 microRNA 被认为是肌肉纤维化相关疾病的有效诊断生物标志物。然而,用于早期诊断挛缩肌肉的循环生物标志物在臀肌挛缩症(GMC)患者中是有限的。在这里,我们试图探索 GMC 患者血浆和挛缩带中异常表达的 microRNA。结果表明,与正常对照组相比,GMC 患者血浆和挛缩带组织中的 miR-29a-3p 表达明显降低。与阴性对照组相比,miR-29a 模拟物可强力抑制细胞活力和增殖相关蛋白细胞周期蛋白 D1 和细胞周期蛋白依赖性激酶 2(CDK2)的水平,而 miR-29a 抑制剂则增强了这些水平。此外,miR-29a 模拟物可有效抑制,而 miR-29a 抑制剂则增强了原代人挛缩带(CB)成纤维细胞中胶原 I 和胶原 III 的表达,随后分泌转化生长因子β1(TGF-β1)、TGF-β3 和结缔组织生长因子(CTGF)。miR-29a-3p 通过与编码热休克蛋白 HSP47 的 SERPINH1 的 3'UTR 区域结合负调控 TGF-β1 的表达,但对 Smad2 活性没有影响。miR-29a-3p 与 GMC 患者挛缩带组织中的 HSP47 呈负相关。总之,miR-29a 在 GMC 中明显下调并通过直接靶向 HSP47 调节细胞活力和纤维化,这表明循环 miR-29a 可能是早期诊断的潜在生物标志物,并为 GMC 提供了一个新的治疗靶点。