MiR-122 and the WNT/β-catenin pathway inhibit effects of both interleukin-1β and tumor necrosisfactor-α in articular chondrocytes in vitro.

Abstract

Interleukin‐1β (IL‐1β), tumor necrosis factor‐α (TNF‐α), and WNT/β‐catenin signaling cause dysregulation of rat primary articular chondrocytes (rArCs), resulting in cartilage extracellular matrix destruction and osteoarthritis (OA) progression. microRNA (miR) miR‐122 represses these effects whereas miR‐451 exacerbates IL‐1β‐stimulated matrix metalloproteinase‐13 (MMP‐13) and prostaglandin E2 (PGE2) production. The goals of this study were to evaluate crosstalk between these signaling pathways and determine if miR‐122 and miR‐451 exert their protective/destructive effects through these pathways in an in vitro model of OA. Primary rArCs were treated with IL‐1β or TNF‐α for 24 h and total DNA, MMP‐13, and PGE2, as well as expression levels of miR‐122 and miR‐451 were measured. After 24‐h transfection with miR‐122, miR‐451, miR‐122‐inhibitor, or miR‐451‐inhibitor, rArCs were treated with or without TNF‐α for 24 h; total DNA, MMP‐13, and PGE2 were measured. Similarly, cells were treated with WNT‐agonist lithium chloride (LiCl), WNT‐antagonist XAV‐939 (XAV), or PKF‐118‐310 (PKF) with and without IL‐1β or TNF‐α stimulation. Both IL‐1β and TNF‐α‐stimulation increased MMP‐13 and PGE2 production. Transfection with miR‐122 prevented TNF‐α‐stimulated increases in MMP‐13 and PGE2 whereas transfection with miR‐451 did not change these levels. No differences were found in MMP‐13 or PGE2 production with miR‐122 or miR‐451 inhibitors. LiCl treatment decreased PGE2 production in cultures treated with TNF‐α, but not MMP‐13. XAV increased TNF‐α‐stimulated increases in PGE2 but not MMP‐13. LiCl reduced IL‐1β‐stimulated increases in MMP‐13 and PGE2. XAV and PKF increased IL‐1β‐stimulated increases in MMP‐13 and PGE2. In this in vitro OA model, miR‐122 protects against both IL‐1β and TNF‐α stimulated increases in MMP‐13 and PGE2 production. miR‐451 does not act through the TNF‐α pathway. The WNT/β‐catenin pathway regulates the effects of IL‐1β and TNF‐α stimulation. This study suggests that miR‐122 can be used as a treatment or prevention for OA.