Abstract
This study was performed to evaluate the contribution of adiponectin to the production of interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-1 and MMP-13 in human endothelial cells and osteoblasts in arthritic joints. Cultured human umbilical vascular endothelial cells (HUVECs) and osteoblasts were stimulated with adiponectin (1 or 10 μg ml−1) or IL-1β (0.1 ng ml−1) in the presence or absence of hypoxia for 24 h. The protein expression patterns were examined by analyzing culture supernatants using the enzyme-linked immunosorbent assay (ELISA). Adiponectin significantly stimulated the production of VEGF, MMP-1 and MMP-13 in osteoblasts but not in endothelial cells, whereas it significantly stimulated the production of IL-6 and IL-8 in both endothelial cells and osteoblasts. The increase in VEGF production induced by adiponectin was significantly greater than that induced by IL-1β. The production of IL-6 and IL-8 in adiponectin-stimulated endothelial cells was approximately 10-fold higher than that in IL-1β-stimulated endothelial cells; in osteoblasts, adiponectin-induced IL-6 and IL-8 secretion was approximately twofold higher than that induced by IL-1β. In addition, IL-8 production in endothelial cells was approximately sevenfold higher than in osteoblasts. However, IL-6 levels were similar between the two cell types, suggesting that adiponectin may be involved in the production of IL-8 in endothelial cells, which may have an important role in neutrophil recruitment to arthritic joints. Furthermore, the increases in protein expression induced by adiponectin were differentially regulated by hypoxia. In conclusion, adiponectin has a more important role than does IL-1β in the production of mediators that drive synovitis and joint destruction in endothelial cells and osteoblasts at physiological concentrations.
Highlights
In rheumatoid arthritis (RA), proliferative fibroblast-like synoviocytes (FLSs) have important roles in progressive damage to articular cartilage and subchondral bone and in the propagation of inflammation
Expression patterns of vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs)-1 and MMP-13 in human endothelial cells and osteoblasts in response to adiponectin The expression of VEGF, MMP-1 and MMP-13, which are involved in matrix degradation and neovascularization, was evaluated in endothelial cells and osteoblasts in response to adiponectin
We evaluated the contributions of endothelial cells and osteoblasts to the production of VEGF, MMP-1, MMP-13, IL-6 and IL-8 in arthritic joints
Summary
In rheumatoid arthritis (RA), proliferative fibroblast-like synoviocytes (FLSs) have important roles in progressive damage to articular cartilage and subchondral bone and in the propagation of inflammation These cells produce many mediators of inflammation, such as cytokines and matrix metalloproteinases (MMPs), which contribute to cartilage degradation in the joints.[1] FLSs are regarded as key players in joint inflammation.[2] In addition to FLSs, other cells such as lymphocytes, chondrocytes, osteoblasts and endothelial cells are partly involved in RA pathophysiology. The perpetuation of neovascularization in RA is highly necessary for leukocyte extravasation into the synovium and pannus formation, which is required for the persistence of RA.[3] Numerous soluble and cell surface-bound angiogenic mediators, including growth factors, cytokines, proteases, matrix macromolecules, cell adhesion receptors, chemokines and chemokine receptors, have been implicated in neovascularization. The exposure of osteoblasts in arthritic joints to inflammation stimulates the production of various inflammatory mediators and MMPs in response to proinflammatory cytokines.[4,5]
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