Overexpression of microRNA-210 promotes chondrocyte proliferation and extracellular matrix deposition by targeting HIF-3α in osteoarthritis

Abstract

The present study aimed to determine the effect of microRNA (miR)‑210 on osteoarthritis (OA). The expression levels of miR‑210, type I and X collagen (COL1A1 and COL10A1) and matrix metallopeptidase 13 (MMP13) in OA and normal chondrocytes were determined using reverse transcription‑quantitative polymerase chain reaction analysis. The OA chondrocytes were transfected with an miRNA precursor for miR‑210 or a negative control. After 3, 7, 14 and 21 days, the expression levels of miR‑210 were examined, the proliferation of the OA chondrocytes were determined using an XTT assay and the protein levels of Ki67 and HIF‑3α were analyzed by Western blotting. After 21 days, the mRNA and protein levels of COL1A1, COL10A1 and MMP13 were analyzed. Th present study demonstrated that the expression levels of miR‑210 and COL1A1 were lower, and the expression levels of COL10A1 and MMP13 were higher in the OA chondrocytes, compared with the levels of expression in the normal chondrocytes. Overexpression of miR‑210 significantly promoted the proliferation of OA chondrocytes and induced the protein expression of Ki67. In addition, miR‑210 overexpression markedly increased the expression of COL1A1 expression, but decreased the expression levels of COL10A1 and MMP13. A luciferase reporter assay confirmed the direct interaction between miR‑210 and hypoxia‑inducible factor (HIF)‑3α. miR‑210 did not alter the mRNA expression of HIF‑3α, however, it suppressed the protein expression of HIF‑3α. Additionally, HIF‑3α knockdown significantly promoted OA chondrocyte proliferation and increased the mRNA levels of COL1A1, whereas it decreased the mRNA levels of COL10A1 and MMP13. The results of the present study suggested that miR‑210 may be a negative regulator of the progression of OA, which increases chondrocyte proliferation and prompts extracellular matrix deposition by directly targeting HIF‑3α.

Onset and Progression of Human Osteoarthritis—Can Growth Factors, Inflammatory Cytokines, or Differential miRNA Expression Concomitantly Induce Proliferation, ECM Degradation, and Inflammation in Articular Cartilage?

“…MiR-210 expression is downregulated in human knee and hip OA AC compared to normal AC [151,219]. Transfection of a miR-210 precursor in human OA AC derived monolayer cell cultures induces COL2A1 mRNA expression, whereas COL10A1 and MMP-13 expression is significantly reduced [219].…”

“…Transfection of a miR-210 precursor in human OA AC derived monolayer cell cultures induces COL2A1 mRNA expression, whereas COL10A1 and MMP-13 expression is significantly reduced [219]. In human cervical cancer cells, SMAD4 has been identified as a direct target of miR-210 [220].…”

The complex landscape of microRNAs in articular cartilage: biology, pathology, and therapeutic targets

“…For instance, miR-210, which is downregulated in OA tissue (26), promotes survival of LPS-treated rat chondrocytes by inhibiting NF-κB signaling and apoptosis (47). In OA chondrocytes miR-210 overexpression inhibits HIF-3α expression, further promoting chondrocyte proliferation and ECM deposition (48). Similarly, injection of miR-210-expressing lentivirus into rats with surgically induced OA reduces select cytokine levels in synovial fluid (47).…”

The Involvement of MicroRNAs in Osteoarthritis and Recent Developments: A Narrative Review

“…36 MicroRNAs involved in cartilage matrix degradation and joint inflammation in OA Dysregulation of the expression of several miRNAs in OA results in increased production of cartilage matrix degrading enzymes (MMPs, ADAMTS proteases). Downregulation of miR-24, miR-27b, miR-148a, miR-210, miR-222, miR-370, miR-373 and miR-488 in OA cartilage leads directly or indirectly to an increase in the production of MMPs, [37][38][39][40][41][42][43] while downregulation of miR-30a, miR-105, miR-125b and miR-148a results in overproduction of ADAMTS proteases. [43][44][45][46] Moreover, upregulation of miR-16-5p and miR-23a-3p leads to upregulation of MMPs and ADAMTS proteases and downregulation of matrix components (type II collagen, aggrecan).…”