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

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. Functional insights into a short RNA strand that prevents cartilage degeneration could lead to new therapeutic strategies for treating osteoarthritis. The microRNA miR-455-3p regulates genes in tissues throughout the body, but Weiming Liao and Zhiqi Zhang of the First Affiliated Hospital of Sun Yat-sen University in Guangzhou, China have observed that it appears to play a particularly prominent role in cartilage-producing chondrocyte cells. Liao, Zhang and colleagues have now explored this mechanism in detail, and determined that miR-455-3p selectively blocks the effects of a protein called PAK2 in chondrocytes. PAK2 normally inhibits an important signaling pathway underlying cartilage generation, and such inhibition has previously been observed in MDCK epithelial cells. The authors conclude that this microRNA or other drugs that replicate its PAK2-inhibiting effects could prevent or slow the joint damage associated with this degenerative disorder.