A long non-coding RNA, GAS5, plays a critical role in the regulation of miR-21 during osteoarthritis

Abstract

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 overexpression 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. ß

Association of long non‑coding RNA GAS5 and miR‑21 levels in CD4+ T cells with clinical features of systemic lupus erythematosus

“…It has been reported that lncRNA GAS5 was negatively regulated by miR-21 in breast tumors, hepatocellular carcinoma and osteoarthritis. GAS5 was also capable of suppressing miR-21 through an lncRNA/miRNA interaction, implying a feedback loop between GAS5 and miR-21 (8,(25)(26)(27). However, in the present study, GAS5 as well as miR-21 were identified to be upregulated in the CD4 + T cells of SLE patients, which may be associated with different types of diseases and cells (8,28,29).…”

“…GAS5 was also capable of suppressing miR-21 through an lncRNA/miRNA interaction, implying a feedback loop between GAS5 and miR-21 (8,(25)(26)(27). However, in the present study, GAS5 as well as miR-21 were identified to be upregulated in the CD4 + T cells of SLE patients, which may be associated with different types of diseases and cells (8,28,29). In the CD4 + T cells of SLE patients, the function of GAS5 may be primarily dependent on glucocorticoids signaling pathways (13).…”

“…GAS5 has been reported to be closely associated with various human diseases (8,28,30). GAS5 functions as a potential tumor suppressor and is downregulated in several types of cancer (28).…”

“…Growth arrest-specific 5 (GAS5), a non-coding gene that hosts a number of small nucleolar RNAs, has been suggested to have numerous important roles in apoptosis and cell growth inhibition. Previous studies have reported that human GAS5 was upregulated in osteoarthritis (OA) patients (8) and downregulated in certain cancer types, including breast cancer (9), renal cell carcinoma (10) and hepatocellular cancer (11). The GAS5 gene locus in the mouse BXSB strain has been linked to increased susceptibility to SLE (12).…”

Rs145204276 polymorphism of GAS5 is associated with renal fibrosis via miR-21/SMAD/TGF-β1 signaling pathway

“…A reciprocal repression of miR-21 and GAS5 has been found during OA pathogenesis. The expression of GAS5 was significantly increased by miR-21 inhibition which leads to the degradation of cartilage [21].…”