Abstract
IntroductionPannus 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)-2α-induced chemokines by chondrocytes in the regulation of fibroblast-like synoviocyte (FLS) migration into the cartilage-pannus interface and cartilage erosion.MethodsCollagen-induced arthritis (CIA), K/BxN serum transfer, and tumor necrosis factor-α transgenic mice were used as experimental RA models. Expression patterns of HIF-2α 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-2α was determined via local deletion of HIF-2α in joint tissues or using conditional knockout (KO) mice. Cartilage destruction, synovitis and pannus formation were assessed via histological analysis.ResultsHIF-2α and various chemokines were markedly upregulated in degenerating cartilage and pannus of RA joints. HIF-2α induced chemokine expression by chondrocytes in both primary culture and cartilage tissue. HIF-2α -induced chemokines by chondrocytes regulated the migration and invasion of FLS. Local deletion of HIF-2α in joint tissues inhibited pannus formation adjacent to cartilage tissue and cartilage destruction caused by K/BxN serum transfer. Furthermore, conditional knockout of HIF-2α in cartilage blocked pannus formation in adjacent cartilage but not bone tissue, along with inhibition of cartilage erosion caused by K/BxN serum transfer.ConclusionOur findings suggest that chemokines induced by IL-1β or HIF-2α in chondrocytes regulate pannus expansion by stimulating FLS migration and invasion, leading to cartilage erosion during RA pathogenesis.
Highlights
Pannus formation and resulting cartilage destruction during rheumatoid arthritis (RA) depends on the migration of synoviocytes to cartilage tissue
Since no links have been established between hypoxia-inducible factor (HIF)-2αinduced chemokines, pannus formation, and cartilage erosion, we focused on the potential role of chondrocytederived chemokines in fibroblast-like synoviocyte (FLS) migration and invasion during RA pathogenesis
HIF-2α is upregulated in both cartilage and pannus of the experimental mouse RA joint To elucidate the possible links and regulatory mechanisms between pannus formation and cartilage erosion, we initially examined HIF-2α expression levels in chondrocytes from cartilage and FLS in pannus of inflamed joint tissues
Summary
Pannus formation and resulting cartilage destruction during rheumatoid arthritis (RA) depends on the migration of synoviocytes to cartilage tissue. We focused on the role of hypoxia-inducible factor (HIF)-2α-induced chemokines by chondrocytes in the regulation of fibroblast-like synoviocyte (FLS) migration into the cartilage-pannus interface and cartilage erosion. Huh et al Arthritis Research & Therapy (2015) 17:302 implicated in joint destruction [7, 8] Production of these factors, in addition to cell–cell interactions, is crucial for progression of RA [8, 9]. Chemokines are key players in inducing directed chemotaxis in nearby responsive cells and are classified into four subfamilies, CXC, CC, CX3C, and XC [14] These signaling proteins are essential for leukocyte trafficking during chronic inflammatory diseases, such as RA, atherosclerosis, and adipose inflammation [15], and stimulate migration, proliferation, and MMP activation in FLS during RA pathogenesis [16]. Chemokines are produced by chondrocytes in cartilage tissues of RA joints [17,18,19], but the potential role of hypoxia-inducible factor (HIF)-2α-induced chemokines in regulation of RA pathogenesis remains to be explored
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.