A Long Non-Coding RNA, GAS5, Plays a Critical Role in the Regulation of miR-21 During Osteoarthritis

Growth Arrest-Specific 5 (GAS5) is known to negatively regulate cell survival and is aberrantly expressed in several cancers. The influence of GAS5 on osteoarthritis (OA) has not been determined. To address this, articular chondrocytes were isolated from relatively normal (Non-OA) and clear OA regions (OA) of cartilage in total knee replacement (TKR) patients and biopsied normal cartilage. We found that GAS5 was up-regulated in OA chondrocytes compared with Non-OA and normal chondrocytes. The over-expression of GAS5 increased the expression levels of several MMPs, such as MMP-2, MMP-3, MMP-9, MMP-13, and ADAMTS-4; stimulated apoptosis; and suppressed autophagic responses. Furthermore, we subsequently identified miR-21 as a regulator of GAS5 during OA pathogenesis. The expression level of miR-21 was significantly reduced in OA patients, and the ectopic expression of GAS5 is capable of suppressing miR-21 induction. Consistent with GAS5 experiments, the introduction of miR-21 stimulated the apoptosis of chondrocytes and inhibited the expression levels of autophagic complexes, including LC-3B. In vivo, we found that the introduction of miR-21 into the cartilage of OA mice significantly stimulated cartilage destruction. Together, these results show that GAS5 contributes to the pathogenesis of OA by acting as a negative regulator of miR-21 and thereby regulating cell survival. (c) 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1628-1635, 2014.