Abstract
Osteoarthritis (OA) is characterized by the progressive destruction of articular cartilage, which is involved in the imbalance between extracellular matrix (ECM) synthesis and degradation. MicroRNA-140-5p (miR-140) is specifically expressed in cartilage and plays an important role in OA-induced matrix degradation. The aim of this study was to investigate (1) whether intra-articular injection of melatonin could ameliorate surgically induced OA in mice and (2) whether melatonin could regulate matrix-degrading enzymes at the posttranscriptional level by targeting miR-140. In an in vitro OA environment induced by interleukin-1 beta (IL-1β), melatonin treatment improved cell proliferation of human chondrocytes, promoted the expression of cartilage ECM proteins (e.g., type II collagen and aggrecan), and inhibited the levels of IL-1β-induced proteinases, such as matrix metalloproteinase 9 (MMP9), MMP13, ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4), and ADAMTS5. Both the microarray and polymerase chain reaction (PCR) experiments revealed that miR-140 was a melatonin-responsive microRNA and melatonin upregulated miR-140 expression, which was suppressed by IL-1β stimulation. In vivo experiments demonstrated that intra-articular injection of melatonin prevented disruptions of cartilage matrix homeostasis and successfully alleviated the progression of surgery-induced OA in mice. Transfection of miR-140 antagomir completely counteracted the antiarthritic effects of melatonin by promoting matrix destruction. Our findings demonstrate that melatonin protects the articular cartilage from OA-induced degradation by targeting miR-140, and intra-articular administration of melatonin may benefit patients suffering from OA.
Highlights
Osteoarthritis (OA) is a chronic degenerative joint disease, which is primarily characterized by progressive destruction of articular cartilage
IL-1β is an important mediator of joint inflammation; does it blunt the synthesis of cartilage extracellular matrix (ECM), it stimulates the expression of matrix-degrading enzymes
Consistent with previous studies, we found that melatonin significantly increased the level of transcriptional factor SOX9 even in IL-1β-treated chondrocytes
Summary
Osteoarthritis (OA) is a chronic degenerative joint disease, which is primarily characterized by progressive destruction of articular cartilage. In the late stages of this pathology, OA-induced joint dysfunction is considered to be a leading cause of disability in elderly people, which creates a huge economic burden on society. The pathogenesis of OA is not yet fully understood, a key factor is the imbalance between extracellular matrix (ECM) synthesis and degradation in cartilage [2]. Chondrocytes, the only cell type in articular cartilage, produce the structural components of the cartilage ECM, type II collagen (Collagen II) and the proteoglycan aggrecan. During OA pathogenesis, chondrocytes become metabolically active to produce matrix-degrading enzymes; these enzymes include members of the matrix metalloproteinase (MMP) and ADAMTS
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