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KMID : 0620920150470120001
Experimental & Molecular Medicine
2015 Volume.47 No. 12 p.1 ~ p.1
Crosstalk between FLS and chondrocytes is regulated by HIF-2¥á-mediated cytokines in arthritis
Huh Yun-Hyun

Lee Gyu-Seok
Song Won-Hyun
Koh Jeong-Tae
Ryu Je-Hwang
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)-2¥á 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-2¥á on FLS and chondrocytes, we applied an in vitro co-culture system using a transwell apparatus. When co-cultured with HIF-2¥á-overexpressing chondrocytes, FLS exhibited increased expression of matrix metalloproteinases and inflammatory mediators, similar to the effects induced by tumor-necrosis factor (TNF)-¥á treatment of FLS. Moreover, chondrocytes co-cultured with HIF-2¥á-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-2¥á-induced effects via distinct secretory mediators using Il6-knockout cells and a TNF-¥á-blocking antibody. The FLS-co-culture-induced gene expression changes in chondrocytes were significantly abrogated by IL-6 deficiency, whereas TNF-¥á 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-2¥á-induced upregulation of specific receptors for TNF-¥á (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-2¥á, and may suggest potential new anti-arthritis therapies.
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