Neutralizing synovial RANKL by local OPG gene therapy in collagen-induced arthritis prevents cartilage erosion through induction of a non-destructive type 2 synovitis

Chondrocytes express RANKL and its receptor RANK, implicating the involvement of this pathway in cartilage damage. However, a direct role of RANKL in cartilage destruction has not yet been identified. Here, we used local and systemic osteoprotegerin (OPG) treatment to inactivate RANKL in different arthritis models. We demonstrated that inactivation of RANKL did not suppress cartilage breakdown in a local T-cell IL-17-induced joint pathology, but completely prevented cartilage erosion in collagen-induced arthritis, which is mediated by T cells and immune complexes. Synovial inactivation of RANKL by local OPG gene therapy in collagen-induced arthritis resulted in a chronic type 2 inflammation characterized by abundant expression of IL-4 and protection of cartilage erosion. Microarray analysis revealed abundant expression of YM1 and arginase, which are specific markers of the macrophage M2 phenotype (alternative activated macrophage). Furthermore, protease specific inhibitors and Fc receptor type II are upregulated by OPG. Changes in expression of catabolic mediators and inhibitors in the synovial infiltrate, including the key catabolic cytokine in cartilage destruction IL-1, contribute to the cartilage protective effect of OPG. These data provide evidence that the cartilage protective effect of OPG in collagen arthritis is mediated by induction of a nondestructive type 2 synovitis.