miR-4262 regulates chondrocyte viability, apoptosis, autophagy by targeting SIRT1 and activating PI3K/AKT/mTOR signaling pathway in rats with osteoarthritis

Abstract

Abstract. The present study aimed to investigate the effect and underlying mechanism of microRNA (miR)-4262 in the development of osteoarthritis (OA) in rats. Primary chondrocytes were separated from Sprague-Dawley rats and then treated with tumor necrosis factor-α (TNF-α). The level of miR-4262 was detected in TNF-α-treated chondrocytes, and then the miR-4262 or its target gene sirtuin type 1 (SIRT1) level was overexpressed, or knocked down. Furthermore, cell viability, cell apoptosis, cell autophagy and matrix synthesis, as well as the expressions of proteins associated with the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway were detected. miR-4262 was significantly overexpressed in TNF-α-treated chondrocytes compared with untreated cells (P<0.05). TNF-α treatment or miR-4262 overexpression significantly decreased cell viability, autophagy-related proteins levels and matrix synthesis-related proteins levels, as well as increased the apoptotic rate in chondrocytes (P<0.05). Overexpression of SIRT1 significantly increased cell viability, autophagy-related proteins levels and matrix synthesis-related proteins levels, as well as decreased the apoptotic rate in TNF-α-treated chondrocytes (P<0.05). In addition, the effects of miR-4262 on cell viability, cell apoptosis, cell autophagy and matrix synthesis were inhibited by SIRT1 (P<0.05). Furthermore, upregulated miR-4262 remarkably increased the expressions of phosphorylated (p)-PI3K, p-AKT and p-mTOR (P<0.05) in TNF-α treated chondrocytes. The present study revealed that the upregulation of miR-4262 may promote the occurrence and development of OA in rats by regulating cell viability, cell apoptosis, cell autophagy, and matrix synthesis. Furthermore, these roles of miR-4262 may be associated with PI3K/AKT/mTOR signaling pathway.

The diagnostic value and pathogenetic role of lncRNA-ATB in patients with osteoarthritis

“…Akt signaling has been proven to be involved in the pathogenesis of osteoarthritis [ 11 ]. In our study, lncRNA-ATB overexpression showed no significant effect on the expression level of Akt in the cells of human chondrocyte cell line CHON-001 (Fig.…”

Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis

“…In primary human and TC28a2 chondrocytes, miR-155 inhibited autophagy and contributed to the autophagy defects in OA (D'Adamo et al, 2016 ). In rats with OA, miR-4262 regulates chondrocyte fate by influencing PI3K/AKT/mTOR signaling (Sun et al, 2018 ). In OA chondrocytes and in zebra fish, Fis1 suppression induces accumulation and inhibition of lysosomes by altering miRNAs and energy signals (Kim et al, 2016 ).…”

The complex landscape of microRNAs in articular cartilage: biology, pathology, and therapeutic targets

“…This miR is induced by IL-1β in rat chondrocytes and promotes apoptosis, induces iNOS expression, and decreases Col2a1 expression (85). miR-4262, which targets SIRT1, is increased in TNF-α-treated rat chondrocytes and promotes chondrocyte apoptosis and inhibits autophagy, contributing to OA pathogenesis (86). Loss of matrix synthesis proteins and elevation of matrix-degrading enzymes, such as MMP-13 and ADAMTS-5, was also observed downstream of miR-4262 (86).…”