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

• Published in: Experimental & molecular medicine Vol. 47; no. 12; p. e197
• Main Authors: Huh, Yun Hyun, Lee, Gyuseok, Song, Won-Hyun, Koh, Jeong-Tae, Ryu, Je-Hwang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2015; Nature Publishing Group
• Subjects: 13; 38/77; 631/80/304; 631/80/86; 64/60; 82/1; 82/80; Animals; Arthritis - genetics; Arthritis - immunology; Arthritis - pathology; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - pathology; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - immunology; Biomedical and Life Sciences; Biomedicine; Cells, Cultured; Chondrocytes - immunology; Chondrocytes - metabolism; Chondrocytes - pathology; Coculture Techniques; Fibroblasts - immunology; Fibroblasts - metabolism; Fibroblasts - pathology; Gene Expression Regulation; Interleukin-6 - genetics; Interleukin-6 - immunology; Male; Medical Biochemistry; Mice; Mice, Inbred C57BL; Molecular Medicine; Original; original-article; Osteoarthritis - genetics; Osteoarthritis - immunology; Osteoarthritis - pathology; Stem Cells; Synovial Membrane - immunology; Synovial Membrane - metabolism; Synovial Membrane - pathology; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology; Up-Regulation
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/emm.2015.88

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)-2α 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-2α on FLS and chondrocytes, we applied an in vitro co-culture system using a transwell apparatus. When co-cultured with HIF-2α-overexpressing chondrocytes, FLS exhibited increased expression of matrix metalloproteinases and inflammatory mediators, similar to the effects induced by tumor-necrosis factor (TNF)-α treatment of FLS. Moreover, chondrocytes co-cultured with HIF-2α-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-2α-induced effects via distinct secretory mediators using Il6- knockout cells and a TNF-α-blocking antibody. The FLS-co-culture-induced gene expression changes in chondrocytes were significantly abrogated by IL-6 deficiency, whereas TNF-α 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-2α-induced upregulation of specific receptors for TNF-α (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-2α, and may suggest potential new anti-arthritis therapies. Joint disease: A common factor for rheumatoid and osteoarthritis Cross-talk between two cell types in the joints appears to underlie tissue damage observed in two different forms of arthritis. Rheumatoid arthritis is caused by inflammatory damage to the synovial membrane surrounding the joints, whereas osteoarthritis entails degradation of the cartilage. Researchers led by Je-Hwang Ryu at Chonnam National University in Korea have found that both conditions may be fueled by a common signaling factor called hypoxia-inducible factor (HIF)-2α, which is overproduced in both disorders. The researchers cultivated cartilage and synovial cells together, and showed that HIF-2α secreted by either cell population stimulated production of inflammatory and tissue-damaging proteins in the other. Subsequent experiments revealed that HIF-2α initiates this response through distinct signaling pathways in synovial and cartilage cells. Importantly, these results suggest that existing drugs for rheumatoid arthritis may benefit osteoarthritis patients as well.