Hypoxia-Inducible Factor-2α Is an Essential Catabolic Regulator of Inflammatory Rheumatoid Arthritis

Je-Hwang Ryu,Ji-Sun Kwak,Sin-Hyeog Im,Youngnim Shin,Churl-Hong Chun,Yun Hyun Huh,Jang-Soo Chun,Young-Myeong Kim,Chang-Suk Chae,Yong-Wook Park,Choong-Gu Lee,Hwanhee Oh,Philippa Marrack

doi:10.1371/journal.pbio.1001881

Abstract

Author SummaryRheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by chronic inflammation in joint tissues leading to destruction of cartilage and bone. Despite some therapeutic advances, the etiology of RA pathogenesis is not yet clear, and effective treatment of RA remains a significant, unmet medical need. Hypoxia is a prominent feature of inflamed tissue within RA-affected joints, and earlier work has implicated limited involvement of hypoxia-inducible factor (HIF)-1 α. We explored the role of a second HIF family member, HIF-2α, in RA pathogenesis. We showed that HIF-2α is markedly increased in the tissue lining the RA-affected joints. Notably and in contrast to HIF-1α, when overexpressed in normal mouse joint tissues, HIF-2α is sufficient to cause RA-like symptoms. Conversely, an HIF-2α deficiency blocks the development of experimental arthritis in mice. We discovered further that HIF-2α regulates RA pathogenesis by modulating various RA-associated functions of joint-specific fibroblast-like cells, including proliferation, expression of cytokines, chemokines, and matrix-degrading enzymes, and bone-remodeling potential. HIF-2α also increases the ability of these cells to promote interleukin-6–dependent differentiation of TH17 cells, a known effector of RA pathogenesis. We thus show that HIF-1α and HIF-2α have distinct roles and act via different mechanisms in RA pathogenesis.

Highlights

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that mainly targets the synovial membrane, resulting in destruction of the joint architecture
Hypoxia is a prominent feature of inflamed tissue within RA-affected joints, and earlier work has implicated limited involvement of hypoxia-inducible factor (HIF)-1 a
We explored the role of a second HIF family member, HIF-2a, in RA pathogenesis

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that mainly targets the synovial membrane, resulting in destruction of the joint architecture. The pathophysiology of RA involves numerous cell types, including T cells, B cells, macrophages, synoviocytes, chondrocytes, and osteoclasts, all of which contribute to the process of RA pathogenesis [1]. FLS actively contribute to the initiation, propagation, and maintenance of synovial inflammation through secretion of factors and direct cell– cell interactions. Cytokines and chemokines produced by FLS attract T cells to RA synovium, and the interaction of FLS with T cells results in activation of both cell types. FLS in the inflamed synovium contribute to RA pathogenesis by producing matrix-degrading enzymes involved in cartilage destruction; RANKL (receptor activator of nuclear factor–kB ligand), which regulates osteoclast differentiation, leading to bone erosion; and angiogenic factors associated with blood vessel formation [4]

Methods

Results

Discussion

Conclusion