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.

Long non-coding RNA Gm37494 alleviates osteoarthritis chondrocyte injury via the microRNA-181a-5p/GABRA1 axis

“…OA is a prevalent joint disease with progressive pain, and the pathogeny of the disease remains unclear [25]. In recent years, the research on OA pathogenesis and treatment has focused on molecular mechanisms involving lncRNAs and miRs [26,27]. This study was designed to gain novel insight into the mechanism of Gm37494 in OA progression with the involvement of miR-181a-5p and GABRA1.…”

“…A growing body of evidence revealed that miR-181a acted as a mediator of cartilage degeneration and participated in the promotion of inflammation and death in chondrocytes [18,34]. Another study also reported that miR-181a-5pdown-regulated growth arrest-specific gene 1 might be a mechanism of OA development [26]. More importantly, prior research elucidated that miR-181a-5p expression was high in IL-1β-treated C28/I2 cells and that ectopic miR-181a-5p neutralized the repressive impacts of circ_0020093 up-regulation on the inflammation and apoptosis of IL-1β-induced C28/I2 cells [35].…”

The enzymatic hydrolysates from deer sinew promote MC3T3-E1 cell proliferation and extracellular matrix synthesis by regulating multiple functional genes

“…Cdc20 is an activator of the anaphase-promoting complex, and is weakly expressed in osteoblasts but highly expressed in the osteocytes [ 37 ]. Gas1 is a cell growth repressor gene that serves as a suppressive regulator of cell growth and as a mediator of apoptosis [ 38 ]. Nrp2 is a family member of the neuropilins, and one of its isoform Nrp2b inhibits cultured cell proliferation [ 39 ].…”

Identification of transcription factors and construction of a novel miRNA regulatory network in primary osteoarthritis by integrated analysis

“…In the study, we screened out 9 up-regulated DEMs and 10 down-regulated DEMs by exploring overlapped DEMs in the PBL of internal samples and synovial tissue of GSE143514 database. Among those up-regulated DEMs, mir-34a-5p could play an important role in the cell progression of osteosarcoma and could induce chondrocyte apoptosis during OA progression [ 26 ]. A previous study reported that mir-138-5p could inhibit the apoptosis and inflammation of chondrocytes and regulate cartilage phenotype and osteogenesis [ 27 ].…”