Exp Mol Med.  2015 Dec;47(12):e197. 10.1038/emm.2015.88.

Crosstalk between FLS and chondrocytes is regulated by HIF-2alpha-mediated cytokines in arthritis

• Huh YH
• Lee G
• Song WH
• Koh JT
• Ryu JH

• KMID: 2359884
• DOI: http://doi.org/10.1038/emm.2015.88

Abstract

Rheumatoid arthritis (RA) and osteoarthritis (OA), two common types of arthritis, affect the joints mainly by targeting the synovium and cartilage. Increasing evidence indicates that a significant network connects synovitis and cartilage destruction during the progression of arthritis. We recently demonstrated that hypoxia-inducible factor (HIF)-2alpha causes RA and OA by regulating the expression of catabolic factors in fibroblast-like synoviocytes (FLS) or chondrocytes. To address the reciprocal influences of HIF-2alpha on FLS and chondrocytes, we applied an in vitro co-culture system using a transwell apparatus. When co-cultured with HIF-2alpha-overexpressing chondrocytes, FLS exhibited increased expression of matrix metalloproteinases and inflammatory mediators, similar to the effects induced by tumor-necrosis factor (TNF)-alpha treatment of FLS. Moreover, chondrocytes co-cultured with HIF-2alpha-overexpressing FLS exhibited upregulation of Mmp3 and Mmp13, which is similar to the effects induced by interleukin (IL)-6 treatment of chondrocytes. We confirmed these differential HIF-2alpha-induced effects via distinct secretory mediators using Il6-knockout cells and a TNF-alpha-blocking antibody. The FLS-co-culture-induced gene expression changes in chondrocytes were significantly abrogated by IL-6 deficiency, whereas TNF-alpha neutralization blocked the alterations in gene expression associated with co-culture of FLS with chondrocytes. Our results further suggested that the observed changes might reflect the HIF-2alpha-induced upregulation of specific receptors for TNF-alpha (in FLS) and IL-6 (in chondrocytes). This study broadens our understanding of the possible regulatory mechanisms underlying the crosstalk between the synovium and cartilage in the presence of HIF-2alpha, and may suggest potential new anti-arthritis therapies.

MeSH Terms

Animals
Arthritis/genetics/*immunology/pathology
Arthritis, Rheumatoid/genetics/immunology/pathology
Basic Helix-Loop-Helix Transcription Factors/genetics/*immunology
Cells, Cultured
Chondrocytes/immunology/metabolism/*pathology
Coculture Techniques
Fibroblasts/immunology/metabolism/*pathology
Gene Expression Regulation
Interleukin-6/genetics/*immunology
Male
Mice
Mice, Inbred C57BL
Osteoarthritis/genetics/immunology/pathology
Synovial Membrane/immunology/metabolism/*pathology
Tumor Necrosis Factor-alpha/genetics/*immunology
Up-Regulation
Basic Helix-Loop-Helix Transcription Factors
Interleukin-6
Tumor Necrosis Factor-alpha