HIF-2α-induced chemokines stimulate motility of fibroblast-like synoviocytes and chondrocytes into the cartilage-pannus interface in experimental rheumatoid arthritis mouse models

Introduction: Pannus formation and resulting cartilage destruction during rheumatoid arthritis (RA) depends on the migration of synoviocytes to cartilage tissue. Here, we focused on the role of hypoxia-inducible factor (HIF)-2 alpha-induced chemokines by chondrocytes in the regulation of fibroblast-like synoviocyte (FLS) migration into the cartilage-pannus interface and cartilage erosion. Methods: Collagen-induced arthritis (CIA), K/BxN serum transfer, and tumor necrosis factor-alpha transgenic mice were used as experimental RA models. Expression patterns of HIF-2 alpha and chemokines were determined via immunostaining, Western blotting and RT-PCR. FLS motility was evaluated using transwell migration and invasion assays. The specific role of HIF-2 alpha was determined via local deletion of HIF-2 alpha in joint tissues or using conditional knockout (KO) mice. Cartilage destruction, synovitis and pannus formation were assessed via histological analysis. Results: HIF-2 alpha and various chemokines were markedly upregulated in degenerating cartilage and pannus of RA joints. HIF-2 alpha induced chemokine expression by chondrocytes in both primary culture and cartilage tissue. HIF-2 alpha-induced chemokines by chondrocytes regulated the migration and invasion of FLS. Local deletion of HIF-2 alpha in joint tissues inhibited pannus formation adjacent to cartilage tissue and cartilage destruction caused by K/BxN serum transfer. Furthermore, conditional knockout of HIF-2 alpha in cartilage blocked pannus formation in adjacent cartilage but not bone tissue, along with inhibition of cartilage erosion caused by K/BxN serum transfer. Conclusion: Our findings suggest that chemokines induced by IL-1 beta or HIF-2 alpha in chondrocytes regulate pannus expansion by stimulating FLS migration and invasion, leading to cartilage erosion during RA pathogenesis.