The role of interleukin-17 and RANKL in the regulation of bone destruction in arthritis

Abstract

Arthritis is a common disease characterised by chronic inflammation as well as bone and cartilage destruction. Proinflammatory cytokines such as interieukin-17( IL-17), aT cell derived cytokine, and Oncostatin M (OSM) a microphage cytokine, are elevated in rheumatoid arthritis (RA). The aim of this study was to characterise the effects of IL-17 and OSM on the expression of receptor activator of NF-kappaBl and (RANKL) and its decoy receptoro steoprotegeri(nO PG)by mesenchymalil neage cells in vitro, in particular synovial fibroblasts and the human osteo sarcoma cell line (MG-63 and SaOS-2) that are potentially involved in this process as they regulate osteoclastogenesis. In addition, the ability of IL-17 to support osteoclastogenesinis vitro was assessed. Human synovial fibroblasts( SFB)from RA and OA patients were contrasted with cell lines MG-63 and SaOS-2 and were treated with IL-17 and/or OSM for up to 48 hr. The expression and production of RANKL and OPG over a time course was assessed in these cells. To investigate osteoclastogenesis peripheral blood mononuclea cells (PBMCs)were cultured with IL-17 either alone or with Macrophage colony stimulating factor (M-CSF). Osteoclastogenesis was analyzed after 21 days by tartrate-resistant acid phosphatase (TRAP),positive multinucleated cell counts, and resorption of ivory slices. This study demonstrated a direct role for IL- 17 in bone and cartilage catabolism through the induction of RANKL and OPG mRNA levels at 6 hr and 48 hr in SFB RA and OA, MG-63 and SaOS-2. Furthermore the combination of IL-17 and OSM showed that the expression of RANKL and OPGw as down-regulated. Co-incubation of IL-17 with or without M-CSF significantly enhanced TRAP+ve multinucleated cell formation. Furthermore cultures of PBMC with IL-17 on ivory slices showed significantly increased resorption and when cocultured with synovial fibroblasts from RA and OA patients further significant resorption. The addition of OPG to IL-17 cultures significantly inhibited the formation of resorption lacunae. The effect of IL-17 on bone resorption in vitro is mostly RANKL-dependent. This finding may lead to the conclusion that IL-17 significantly induces osteoclasto genesis in vitro. Therefore,I L-17 represents a key cytokine involved in the exacerbation of inflammatory joint disease and is an important target for anti-cytokine therapies. Also these results provide proof of the concept that OPG production can result in effective therapies.