The role of adiponectin in the production of IL-6, IL-8, VEGF and MMPs in human endothelial cells and osteoblasts: implications for arthritic joints

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. Adiponectin, a signaling factor produced by adipocytes, the major cell type in body fat, triggers an inflammatory response that may contribute to rheumatoid arthritis (RA). Previously, Kyoung Soo Kim and colleagues at South Korea's Kyung Hee University found that joint damage may be accelerated by the effects of adiponectin on specialized cells known as fibroblast-like synoviocytes. In a follow-up study, the researchers explored how adiponectin affects other cell types found within joints. They determined that blood vessel-derived endothelial cells treated with physiologically-relevant doses of adiponectin release high levels of interleukin-8, a signaling molecule that recruits inflammation-promoting immune cells. In osteoblasts — cells responsible for building bone — the researchers showed that adiponectin stimulates the production of matrix metalloproteinase-1 and -13. These two enzymes can degrade joint cartilage and may thus represent another mechanism for adiponectin-mediated RA progression.