Abstract
Arthritis is a process of chronic inflammation that results in joint damage. IL (interleukin)-1β is an inflammatory cytokine that acts as a key mediator of cartilage degradation, and is abundantly expressed in arthritis. Neovascularization is one of the pathological characteristics of arthritis. However, the role of IL-1β in the angiogenesis of chondrocytes remains unknown. In the present study, we demonstrate that stimulating chondrocytes (ATDC5) with IL-1β increased the expression of FGF (fibroblast growth factor)-2, a potent angiogenic inducer, and then promoted EPC (endothelial progenitor cell) tube formation and migration. In addition, FGF-2-neutralizing antibody abolished ATDC5-conditional medium-mediated angiogenesis in vitro, as well as its angiogenic effects in the CAM (chick chorioallantoic membrane) assay and Matrigel plug nude mice model in vivo. IHC (immunohistochemistry) staining from a CIA (collagen-induced arthritis) mouse model also demonstrates that arthritis increased the expression of IL-1β and FGF-2, as well as EPC homing in articular cartilage. Moreover, IL-1β-induced FGF-2 expression via IL-1RI (type-1 IL-1 receptor), ROS (reactive oxygen species) generation, AMPK (AMP-activated protein kinase), p38 and NF-κB (nuclear factor κB) pathway has been demonstrated. On the basis of these findings, we conclude that IL-1β promotes FGF-2 expression in chondrocytes through the ROS/AMPK/p38/NF-κB signalling pathway and subsequently increases EPC angiogenesis. Therefore IL-1β serves as a link between inflammation and angiogenesis during arthritis.
Highlights
Arthritis is a process of joint dysfunction, with acute or longterm inflammation that afflicts one or more joints of the patient
Pre-treatment with type-1 IL-1 receptor (IL-1RI) neutralizing antibody (NAb) attenuated IL-1β-induced fibroblast growth factor (FGF)-2 expression (Figures 1E and 1F). These results indicate that IL-1β induces FGF-2 expression in chondrocytes through IL-1RI
IL-1β-induced FGF-2 expression promotes endothelial progenitor cell (EPC) migration and tube formation ATDC5 cells were incubated with IL-1β at different dosages for 24 h, pre-treated with FGF-2 NAb for 30 min before incubation with IL-1β for 24 h, or incubated with IL-1β for the indicated times
Summary
Arthritis is a process of joint dysfunction, with acute or longterm inflammation that afflicts one or more joints of the patient. The most common forms of arthritis are OA (osteoarthritis) and RA (rheumatoid arthritis). The symptoms of arthritis include swelling, pain, joint stiffness and eroded cartilage [1]. Several factors are associated with an increased risk of arthritis, including aging, obesity, genetic factors and joint injury [2]. Abnormal reactions of the immune system and Abbreviations: AMPK, AMP-activated protein kinase; Ara A, adenine 9-β-D-arabinofuranoside; bCII, bovine type II collagen; CAM, chick chorioallantoic membrane; CFA, complete Freund’s adjuvant; CIA, collagen-induced arthritis; CM, culture medium; DPI, diphenyleneiodonium chloride; EPC, endothelial progenitor cell; FGF, fibroblast growth factor; H2DCFDA, 2 ,7 -dichlorofluorescin diacetate; HRP, horseradish peroxidase; IFA, incomplete Freund’s adjuvant; IHC, immunohistochemistry; IL, interleukin; IL-1RI, type-1 IL-1 receptor; NAb, neutralizing antibody; NAC, N-acetyl-L-cysteine; NF-κB, nuclear factor κB; OA, osteoarthritis; PDTC, ammonium pyrrolidinedithiocarbamate; RA, rheumatoid arthritis; ROS, reactive oxygen species; TPCK, N-p-tosyl-L-phenylalanine chloromethylketone; VEGF, vascular endothelial growth factor; VEGFR2, VEGF receptor 2. The underlying mechanisms and the pathogenesis of arthritis remain unknown
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