The potential role of adiponectin in driving arthritis

Background

Recent data indicate that adipose tissue synthesizes and releases numerous immunocompetent molecules such as tumor necrosis factor (TNF) alpha, C3a and C1-inhibitor. As adipose tissue is also part of rheumatoid joints, we examined whether adiponectin (apM-1), which has structural homologies to complement proteins and members of the TNF family, and its receptors are present in rheumatoid arthritis (RA) and osteoarthritis (OA) synovium. In addition, owing to the ability of adiponectin to exert several immunmodulatory functions, the effect and regulation of adiponectin-dependent synthesis of proinflammatory and antiinflammatory cytokines was examined.

Methods

Snap-frozen synovial sections of patients with RA, OA and articular adipose tissue were evaluated by adiponectin and adiponectin receptors type 1 and 2-specific primers, by in situ hybridization using adiponectin riboprobes and antibodies against adiponectin in combination with double-labeling for fibroblasts. In addition, fresh synovial fibroblasts derived from RA and OA patients undergoing knee joint endoprothetic surgery were stimulated with adiponectin in concentrations from 0.2 to 100 μg/ml for 15 hours and compared with unstimulated fibroblasts. Supernatants were examined for production of IL-1β, IL-4, IL-6, IL-10, matrix metalloproteinase (MMP)-1 and MMP-3 by commercially available ELISA.

Results

In all patients, strong expression of adiponectin mRNA could be detected in synovial lining and to a lesser extent in synovial sublining. Double-labeling with anti-vimentin (fibroblasts) showed that up to 60% of RA fibroblasts expressed the adiponectin gene and adiponectin type 1 and 2 receptors. Stimulation of synovial fibroblasts with adiponectin showed a dose-dependent upregulation of IL-6 and MMP-1, both in RA and OA synovial fibroblasts. Whereas treatment without or with a small concentration of adiponectin (0.2 μg/ml) resulted only in a low production of IL-6, a concentration-dependent increase could be found with the highest amount produced with 100 μg/ml adiponectin. In contrast, synthesis of IL-1β, IL-4, and IL-10 was not altered by adiponectin stimulation. Of interest, both the TNF inhibitors adalimumab and etanercept were able to downregulate adiponectin-dependent IL-6 and MMP-1 synthesis significantly.

Conclusions

The results show that adipocytokines such as adiponectin are not only present in arthritic synovium, but also that adiponectin has stimulatory effects both on the production of distinct cytokines (e.g. IL-6) and of matrix-degrading enzymes (e.g. MMP-1) in synovial fibroblasts. Therefore, the data support the hypothesis that adiponectin may alter the expression of local synovial cytokines and thus may not only represent a candidate gene of a complement/TNF-related pathway operative in RA, but also one of the targets of TNF inhibitor therapy.