microRNA-mediated GAS1 downregulation promotes the proliferation of synovial fibroblasts by PI3K-Akt signaling in osteoarthritis.

Abstract

Hyperplastic synovial fibroblasts (SFs) serve a critical role in the pathogenesis of knee osteoarthritis (OA); however, the molecular mechanism involved in OA during synovial tissue hyperproliferation remains unclear. Growth arrest-specific gene 1 (GAS1), a cell growth repressor gene, was found to be downregulated in OASFs according to previous preliminary experiments. It was therefore hypothesized that reduced GAS1 expression may participate in the hyperproliferation of SFs in OA development, downstream of possible microRNA (miR) regulation, in hyperplastic OASFs. In the present study, GAS1 expression was indeed decreased in OASFs and interleukin-1β-induced SFs by reverse transcription-quantitative PCR and western blot analysis. Further cell viability assays, cell cycle and apoptosis analyses revealed that the overexpression of GAS1 can inhibited proliferation, induced cell cycle arrest and promoted apoptosis in SFs. In contrast, GAS1 knockdown in SFs accelerated cell proliferation, enhanced cell cycle progression and suppressed apoptosis. Notably, the suppressive effects of GAS1 were mediated through the inactivation of the PI3K-Akt pathway. Finally, miR-34a-5p and miR-181a-5p were predicted and subsequently verified to directly target the 3'-untranslated region of the GAS1 gene, downregulating GAS1 levels in OASFs and IL-1β-induced SFs. In conclusion, the present study demonstrated that downregulation of GAS1 can lead to the hyperproliferation of SFs in OA pathogenesis through the PI3K-Akt pathway, and miR-34a-5p and miR-181a-5p are potential regulators of GAS1 expression in OA. Therefore, it may be promising to investigate the potential of GAS1 as a novel therapeutic target for preventing SF hyperplasia in OA.

• Authors: Chuan Dong, Xinli Wang, Nan Li, Kailiang Zhang, Xiaoyan Wang, Haomeng Zhang, Haipeng Wang, Bo Wang, Ming An, Baoan Ma
• Journal: Experimental and therapeutic medicine (Exp Ther Med) Vol. 18 Issue 6 Pg. 4273-4286 (Dec 2019) ISSN: 1792-0981 [Print] Greece
• PMID: 31777535 (Publication Type: Journal Article)
• Copyright: Copyright: © Dong et al.