Estrogen-related receptor \u03b3 causes osteoarthritis by upregulating extracellular matrix-degrading enzymes

Young-Ok Son,Ji-Sun Kwak,Je-Hwang Ryu,Hueng-Sik Choi,Don-Kyu Kim,Jang-Soo Chun,Yoonkyung Won,Wan-Su Choi,Jinseol Rhee,Seulki Park,Churl-Hong Chun

doi:10.1038/s41467-017-01868-8

Abstract

The estrogen-related receptor (ERR) family of orphan nuclear receptor is composed of ERRα, ERRβ, and ERRγ, which are known to regulate various isoform-specific functions under normal and pathophysiological conditions. Here, we investigate the involvement of ERRs in the pathogenesis of osteoarthritis (OA) in mice. Among ERR family members, ERRγ is markedly upregulated in cartilage from human OA patients and various mouse models of OA. Adenovirus-mediated overexpression of ERRγ in mouse knee joint or transgenic expression of ERRγ in cartilage leads to OA. ERRγ overexpression in chondrocytes directly upregulates matrix metalloproteinase (MMP)-3 and MMP13, which are known to play crucial roles in cartilage destruction in OA. In contrast, genetic ablation of Esrrg or shRNA-mediated downregulation of Esrrg in joint tissues abrogates experimental OA in mice. Our results collectively indicate that ERRγ is a novel catabolic regulator of OA pathogenesis.

Highlights

The estrogen-related receptor (ERR) family of orphan nuclear receptor is composed of ERRα, ERRβ, and ERRγ, which are known to regulate various isoform-specific functions under normal and pathophysiological conditions
We previously demonstrated that hypoxia-inducible factor (HIF)-2α, which is transcriptionally upregulated in chondrocytes by proinflammatory cytokines or mechanical stress, causes OA pathogenesis through upregulation of matrix-degrading enzymes[10,11]
Our quantitative reverse transcription-polymerase chain reaction analyses revealed that ERRγ was significantly increased in OAaffected, damaged regions of human cartilage compared with undamaged regions of arthritic cartilage (Fig. 1a)

Summary

Introduction

The estrogen-related receptor (ERR) family of orphan nuclear receptor is composed of ERRα, ERRβ, and ERRγ, which are known to regulate various isoform-specific functions under normal and pathophysiological conditions. The functions of ERRs in regulating joint cartilage homeostasis and/or OA pathogenesis have not yet been studied, an in vitro study by Bonnelye et al.[32] suggested a possible association of ERRα with OA pathogenesis. They demonstrated that IL-1β in human OA chondrocytes upregulates ERRα, which directly targets genes encoding MMP3 and SOX9

Methods

Results

Conclusion