microRNA‐186 inhibition of PI3K–AKT pathway via SPP1 inhibits chondrocyte apoptosis in mice with osteoarthritis

Abstract

Chondrocyte apoptosis has been implicated as a major pathological osteoarthritis (OA) change in humans and experimental animals. We evaluate the ability of miR-186 on chondrocyte apoptosis and proliferation in OA and elucidate the underlying mechanism concerning the regulation of miR-186 in OA. Gene expression microarray analysis was performed to screen differentially expressed messenger RNAs (mRNAs) in OA. To validate the effect of miR-186 on chondrocyte apoptosis, we upregulated or downregulated endogenous miR-186 using mimics or inhibitors. Next, to better understand the regulatory mechanism for miR-186 governing SPP1, we suppressed the endogenous expression of SPP1 by small interfering RNA (siRNA) against SPP1 in chondrocytes. We identified SPP1 is highly expressed in OA according to an mRNA microarray data set GSE82107. After intra-articular injection of papain into mice, the miR-186 is downregulated while the SPP1 is reciprocal, with dysregulated PI3K-AKT pathway in OA cartilages. Intriguingly, miR-186 was shown to increase chondrocyte survival, facilitate cell cycle entry in OA chondrocytes, and inhibit chondrocyte apoptosis in vitro by modulation of pro-and antiapoptotic factors. The determination of luciferase activity suggested that miR-186 negatively targets SPP1. Furthermore, we found that the effect of miR-186 suppression on OA chondrocytes was lost when SPP1 was suppressed by siRNA, suggesting that miR-186 affected chondrocytes by targeting and depleting SPP1, a regulator of PI3K-AKT pathway. Our findings reveal a novel mechanism by which miR-186 inhibits chondrocyte apoptosis in OA by interacting with SPP1 and regulating PI3K-AKT pathway. Restoring miR-186 might be a future therapeutic strategy for OA. K E Y W O R D S apoptosis, chondrocyte, microRNA-186, osteoarthritis, PI3K-AKT pathway, proliferation, SPP1

Circular RNA CSNK1G1 promotes the progression of osteoarthritis by targeting the miR‑4428/FUT2 axis

“…Several miRNAs have been proven to regulate various signaling pathways, apoptosis and chondrocyte functions in OA (28). Some miRNAs are differentially expressed during the onset and development of OA (29)(30)(31). A total of 42 circRNAs have also been found to be differentially expressed in OA (32).…”

Identification of Potential Biomarkers and Survival Analysis for Head and Neck Squamous Cell Carcinoma Using Bioinformatics Strategy: A Study Based on TCGA and GEO Datasets

“…Through the study of related literature, we found that miR-186 inhibits osteoarthritis chondrocyte apoptosis by interacting with SPP1 and regulating the Phosphatidylinositol‐ 3 kinase (PI3K)/protein kinase B (Akt) pathway. The present study also demonstrates that SPP1 is an important regulator of the PI3K-Akt pathway [32]. As an important signaling pathway related to HNSCC occurrence and development, PI3K-Akt highly affects cell progression, proliferation, migration and survival, and may be activated by G1/S of cell cycle [33], which is also closely related to the occurrence and development of tumors[34].…”

miRNA Mechanisms Underlying the Association of Beta Blocker Use and Bone Mineral Density

“…( 54 ) miR‐186 has been shown to inhibit cathepsin K and the PI3K‐AKT pathway in mice, affecting osteoarthritis and drug‐induced bone deterioration. ( 55,56 ) miR‐19a‐3p and miR‐186‐5p are expressed in bone, brain, and spinal cord tissue as well as in whole blood, ( 57 ) so it is reasonable that these miRNAs may be acting on bone or the SNS (Supplemental Fig. S4 A ).…”