MicroRNA-455-3p promotes TGF-\u03b2 signaling and inhibits osteoarthritis development by directly targeting PAK2

Shu Hu,Zhiqi Zhang,Xingzhao Wen,Chengyun Zhang,Ziji Zhang,Weiming Liao,Guping Mao,Xiaoyi Zhao

doi:10.1038/s12276-019-0322-3

Abstract

MicroRNAs (miRNAs, miR) play a key role in the pathogenesis of osteoarthritis (OA). Few studies have examined the regulatory role of P21-activated kinases (PAKs), a family of serine/threonine kinases, in OA. The aim of this study was to determine whether miR-455-3p can regulate cartilage degeneration in OA by targeting PAK2. MiR-455-3p knockout mice showed significant degeneration of the knee cartilage. MiR-455-3p expression increased and PAK2 expression decreased in the late stage of human adipose-derived stem cell (hADSC) chondrogenesis and in chondrocytes affected by OA. Furthermore, in both miR-455-3p-overexpressing chondrocytes and PAK2-suppressing chondrocytes, cartilage-specific genes were upregulated, and hypertrophy-related genes were downregulated. A luciferase reporter assay confirmed that miR-455-3p regulates PAK2 expression by directly targeting the 3′-untranslated regions (3′UTRs) of PAK2 mRNA. IPA-3, a PAK inhibitor, inhibited cartilage degeneration due to OA. Moreover, suppressing PAK2 promoted R-Smad activation in the TGF/Smad signaling pathway in chondrocytes. Altogether, our results suggest that miR-455-3p promotes TGF-β/Smad signaling in chondrocytes and inhibits cartilage degeneration by directly suppressing PAK2. These results thus indicate that miR-455-3p and PAK2 are novel potential therapeutic agents and targets, respectively, for the treatment of OA.

Highlights

Osteoarthritis (OA), characterized by osteophyte formation and articular cartilage degradation, is the leading cause of chronic disability in older adults[1]
We report the role of PAK2 in OA chondrocytes and demonstrate that miR-455-3p promotes TGF-β signaling and inhibits cartilage degeneration in OA chondrocytes by directly targeting PAK2
We demonstrated that miR-455-3p regulates chondrogenesis in ATDC58

Summary

Introduction

Osteoarthritis (OA), characterized by osteophyte formation and articular cartilage degradation, is the leading cause of chronic disability in older adults[1]. The TGF-β/Smad signaling pathway is an important regulator of cartilage anabolism. This pathway can enhance the synthesis of type II collagen and aggrecan, and prevent cartilage degradation[9,10]. TGF-β/Smad signaling is initiated by ligand binding to the type II receptor, which subsequently phosphorylates the type I receptors, both of which are serine/threonine kinase receptors. The activated receptor complex phosphorylates receptor-regulated Smad proteins (RSmad: Smad2/3). The phosphorylated R-Smad associates with Smad[4] to form a complex that

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