Abstract
Osteoarthritis (OA) is a most common form of arthritis worldwide leading to significant disability. MicroRNAs (miRNAs) are non‐coding RNAs involved in various aspects of cartilage development, homoeostasis and pathology. Several miRNAs have been identified which have shown to regulate expression of target genes relevant to OA pathogenesis such as matrix metalloproteinase (MMP)‐13, cyclooxygenase (COX)‐2, etc. Epigallocatechin‐3‐O‐gallate (EGCG), the most abundant and active polyphenol in green tea, has been reported to have anti‐arthritic effects, however, the role of EGCG in the regulation of miRNAs has not been investigated in OA. Here, we showed that EGCG inhibits COX‐2 mRNA/protein expression or prostaglandin E2 (PGE 2) production via up‐regulating microRNA hsa‐miR‐199a‐3p expression in interleukin (IL)‐1β‐stimulated human OA chondrocytes. This negative co‐regulation of hsa‐miR‐199a‐3p and COX‐2 by EGCG was confirmed by transfection of OA chondrocytes with anti‐miR‐199a‐3p. Transfection of OA chondrocytes with anti‐miR‐199a‐3p significantly enhanced COX‐2 expression and PGE 2 production (P < 0.001), while EGCG treatment significantly inhibited anti‐miR‐199a‐3p transfection‐induced COX‐2 expression or PGE 2 production in a dose‐dependent manner. These results were further re‐validated by co‐treatment of these transfection OA chondrocytes with IL‐1β and EGCG. EGCG treatment consistently up‐regulated the IL‐1β‐decreased hsa‐miR‐199a‐3p expression (P < 0.05) and significantly inhibited the IL‐1β‐induced COX‐2 expression/PGE 2 production (P < 0.05) in OA chondrocytes transfected with anti‐hsa‐miR‐199a‐3p. Taken together, these results clearly indicate that EGCG inhibits COX‐2 expression/PGE 2 production via up‐regulation of hsa‐miR‐199a‐3p expression. These novel pharmacological actions of EGCG on IL‐1β‐stimulated human OA chondrocytes provide new suggestions that EGCG or EGCG‐derived compounds inhibit cartilage breakdown or pain by up‐regulating the expression of microRNAs in human chondrocytes.
Highlights
MicroRNAs are a class of small, non-coding RNAs that regulate mRNA expression at the post-transcriptional level
Our results show that primary chondrocytes maintained their behaviours, when they were plated (1.2 9 106/ml) in 35 mm culture dishes, as judged by the continued expression of Col2A1, ACAN and SOX-9 mRNAs
Transfection of OA chondrocytes with anti-miR-199a-3p transfection effectively further increased the IL-1b-induced prostaglandin E2 (PGE2) (P < 0.01) in OA chondrocytes. This enhanced expression of PGE2 production was consistently inhibited by EGCG in a dose-dependent manner (Fig. 3D; P < 0.05). These results clearly indicate that EGCG inhibits COX-2 expression/PGE2 production via up-regulation of hsa-miR-199a-3p expression
Summary
MicroRNAs (miRNAs) are a class of small, non-coding RNAs that regulate mRNA expression at the post-transcriptional level. It is assumed that miRNAs regulate ~60% of all protein coding genes in humans and participate in the regulation of almost every cellular events investigated to date [1, 2]. The importance of miRNAs in maintaining cartilage homoeostasis during development and their dysregulated expression have recently linked with joint pathologies [2, 3]. Dicer is an important component for biogenesis of miRNAs was found to have an essential function in skeletal development. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine
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