LncRNA MALAT1/MiR-145 Adjusts IL-1β-Induced Chondrocytes Viability and Cartilage Matrix Degradation by Regulating ADAMTS5 in Human Osteoarthritis

Abstract

Accumulating evidence suggests that microRNA-145 (miR-145) plays an important role in osteoarthritis (OA), which is a chronic progressive joint disease. Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes metastasis in cancers and functions as a sponge for miR-145. However, the role of MALAT1/miR-145 in OA pathogenesis has not yet been elucidated. Materials and Methods: The expression of MALAT1 and miR-145 was examined by quantitative real-time PCR; the interaction between miR-145, MALAT1 and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 5 was verified by luciferase reporter assay. Correlations among MALAT1, miR-145, and ADAMTS5 were analyzed by Spearman rank analysis. Chondrocytes viability and cartilage extracellular matrix (ECM) degradation were investigated with cell viability assay and Western blotting analyzing expression of ADAMTS5, collagen type 2 alpha 1 (COL2A1), aggrecan (ACAN), and cartilage oligomeric matrix protein (COMP). Results: MALAT1 was upregulated, and miR-145 was downregulated in OA samples and IL-1β-induced chondrocytes. Mechanically, miR-145 could directly bind to MALAT1 and ADAMTS5. Moreover, miR-145 expression was negatively correlated with MALAT1 and ADAMTS5 expression in OA patients, whereas MALAT1 and ADAMTS5 expression was positively correlated. Functionally, overexpression of MALAT1 inhibited chondrocyte viability and promoted cartilage ECM degradation in IL-1β-induced chondrocytes. In support thereof, MALAT1 silencing and miR-145 upregulation exerted the opposite effect in IL-1β-induced chondrocytes. Moreover, the effect of MALAT1 was counteracted by miR-145 upregulation, and ADAMTS5 restoration could abate miR-145 effects. Conclusion: An MALAT1/miR-145 axis contributes to ECM degradation in IL-1β-induced chondrocytes through targeting AD-AMTS5, suggesting that MALAT1/miR-145/ADAMTS5 signaling may underlie human OA pathogenesis.

Overexpression of long non-coding RNA AP001505.9 inhibits human hyaline chondrocyte dedifferentiation

“…LncRNAs can participate in the regulation of gene expression through a variety of mechanisms, such as gene imprinting, chromatin remodeling, and regulation of mRNA precursor splicing, degradation, and translation [ 25 ]. However, lncRNAs also act as ceRNAs by sponging target miRNAs, thus promoting the expression of target genes [ 43 , 44 ]. SOX-9 is an HMG-box (high mobility group box) transcription factor that plays an essential role in chondrocyte development by directing the expression of chondrocyte-specific genes [ 44 ].…”

Zinc and Cadmium in the Aetiology and Pathogenesis of Osteoarthritis and Rheumatoid Arthritis

“…In both OA and RA, inflammatory cytokines such as IL-1β and TNF-α stimulate the production of matrix metalloproteinases (MMPs), such as MMP-1, -3, -8, -9, -13, and ADAMTS5 [ 30 , 31 , 32 , 33 , 34 , 35 ]. MMPs are a family of zinc-dependent proteins, which accumulate in the synovium during inflammation and have a central role in cartilage destruction in arthritis [ 36 ].…”

Small Non-Coding RNAome of Ageing Chondrocytes

“…In addition, circulating miR-143 was upregulated in young individuals following resistant exercise, but was downregulated in older individuals after resistant exercise [67]. MiR-145 was downregulated in old OA patients [68] as well as in experimental OA rat chondrocytes treated with tumour necrosis factor (TNF) [69] and, finally, miR-181b was downregulated in skeletal muscle of old rhesus monkeys [70].…”