microRNA‐206 is required for osteoarthritis development through its effect on apoptosis and autophagy of articular chondrocytes via modulating the phosphoinositide 3‐kinase/protein kinase B‐mTOR pathway by targeting insulin‐like growth factor‐1

Abstract

microRNA (miR) has been shown to be involved in the treatment of diseases such as osteoarthritis (OA). This study aims to investigate the role of miR‐206 in regulating insulin‐like growth factor‐1 (IGF‐1) in chondrocyte autophagy and apoptosis in an OA rat model via the phosphoinositide 3‐kinase (P13K)/protein kinase B (AKT)‐mechanistic target of rapamycin (mTOR) signaling pathway. Wistar rats were used to establish the OA rat model, followed by the observation of histopathological changes, Mankin score, and the detection of IGF‐1‐positive expression and tissue apoptosis. The underlying regulatory mechanisms of miR‐206 were analyzed in concert with treatment by an miR‐206 mimic, an miR‐206 inhibitor, or small interfering RNA against IGF‐1 in chondrocytes isolated from OA rats. Then, the expression of miR‐206, IGF‐1, and related factors in the signaling pathway, cell cycle, and apoptosis, as well as inflammatory factors, were determined. Subsequently, chondrocyte proliferation, cell cycle distribution, apoptosis, autophagy, and autolysosome were measured. OA articular cartilage tissue exhibited a higher Mankin score, promoted cell apoptotic rate, increased expression of IGF‐1, Beclin1, light chain 3 (LC3), Unc‐51‐like autophagy activating kinase 1 (ULK1), autophagy‐related 5 (Atg5), caspase‐3, and Bax, yet exhibited decreased expression of miR‐206, P13K, AKT, mTOR, and Bcl‐2. Besides, miR‐206 downregulated the expression of IGF‐1 and activated the P13K/AKT signaling pathway. Moreover, miR‐206 overexpression and IGF‐1 silencing inhibited the interleukins levels (IL‐6, IL‐17, and IL‐18), cell apoptotic rate, the formation of autolysosome, and cell autophagy while promoting the expression of IL‐1β and cell proliferation. The findings from our study provide a basis for the efficient treatment of OA by investigating the inhibitory effects of miR‐206 on autophagy and apoptosis of articular cartilage in OA via activating the IGF‐1‐mediated PI3K/AKT‐mTOR signaling pathway.

Bone marrow mesenchymal stem cell–derived exosomal miR‐206 promotes osteoblast proliferation and differentiation in osteoarthritis by reducing Elf3

“…miR‐206 can regulate IGF‐1 in chondrocyte autophagy and apoptosis of OA rats. 18 Moreover, miR‐206/cyclin D1 (CCND1) axis is involved in chondrocyte growth during the occurrence and development of OA. 19 Elf3 is a transcription factor induced by inflammatory factors in various cell types including chondrocytes.…”

“… 36 Additionally, Yu et al have provided evidence that the elevation of miR‐206 promoted proliferation and repressed apoptosis of chondrocytes during the development of OA. 18 …”

Osteoarthritis year in review: genetics, genomics, epigenetics

“…In addition to miR-140-5p and miR-146a, other miR that promoted autophagy in chondrocytes include miR-34a-5p, miR-107, miR-335-5p and miR-let-7e [45][46][47][48]. MicroRNAs that decreased autophagic processes include miR-206, miR-375, miR-411, and miR-449 [49][50][51][52].…”

Modulated Autophagy by MicroRNAs in Osteoarthritis Chondrocytes

“…This pathway encompasses a series of associated genes, proteins, or cytokines, explaining why miRNAs have effects on autophagy by targeting these factors. For instance, researchers have recently clarified the negative regulation of miR-206 targeting insulin-like growth factor-1 (IGF-1) in autophagy through this pathway [62]. Another notable miRNA is miR-20 [63], whose mechanisms in the PI3K/AKT/mTOR pathway are similar to those of miR-206.…”

“…Gene interference by miRNAs has become a promising and required direction in the therapy of maintenance of autophagy. Interventions in several known miRNAs have been conducted in both in vitro and in vivo models, such as miR-206 inhibitor and miR-128a antisense oligonucleotide [62, 64], ultimately achieving satisfactory autophagy recovery and chondrocyte survival. However, autophagy is not the sole factor that determines the fate of chondrocytes.…”