Inflammation and bone destruction in arthritis: synergistic activity of immune and mesenchymal cells in joints

Abstract

Rheumatoid arthritis (RA) is an immune-mediated disease of the joints that is characterized by chronic inflammation and synovial hyperplasia that eventually lead to cartilage and bone destruction. Synovial fibroblasts are mesenchymal cells recognized as a key cell population in RA due to their hyperproliferative and hypersensitive properties in the inflammatory milieu and hyperproduction of both inflammatory cytokines and matrix-degrading enzymes. On the immune cell side, a wealth of evidence has shown that CD4(+)T-cells, especially IL-17 producing helper T (Th17) cells, play a prominent role, particularly in the initiation of systemic immune response in RA. However, it is still unclear how the local chronic inflammation in the joint is elicited by a systemic immune response. Recent studies have shed light on the importance of the interaction between immune and mesenchymal cells in joints including synovial fibroblasts. In particular, mesenchymal cells contribute to the Th17-mediated chronic inflammation in RA by promoting the migration of Th17 cells to the inflamed site and then the homeostatic proliferation and concomitant increase in IL-17 production. In addition, recent progress in osteoimmunology has provided new insight into the pathogenesis of the bone destruction which takes place in RA. Th17-related cytokines have been shown to enhance osteoclastogenesis, mainly via synovial fibroblasts. Thus, mesenchymal cells are a determinant of the development of RA that links the systemic immune response and the local disorder in the joints. In addition, the interaction of immune and mesenchymal cells plays a key role in both the chronic inflammation and bone destruction seen in RA. Elucidation of the precise events involved in this interaction will lead to a better understanding of the mechanisms by which chronic inflammation and bone destruction in joint results from a systemic immune response, and also will help provide a molecular basis for novel therapeutic strategies to treat RA.

Keywords: CD4+T-cell; Th17 cell; bone destruction; inflammation; osteoclast; rheumatoid arthritis; synovial fibroblast.

Figure 1

Possible mechanisms of the initiation, inflammatory, and bone destruction phases in RA. A variety of different cell populations, including lymphocytes, innate immune cells, synovial fibroblasts, and osteoclasts, play a role in the development of RA. Th17 cells contribute to the development of arthritis in each of the initiation, inflammatory, and bone destructive phases through the production of autoantibodies as well as the activation of innate immunity and synovial fibroblasts, and then ultimately, bone destruction. Importantly, synovial fibroblasts contribute to Th17 immunity in the inflammatory phase of arthritis by promoting the migration of Th17 cells into the inflammatory joint, and then homeostatic proliferation with an increase in IL-17 production. Thus, the interaction of CD4⁺T-cells and mesenchymal cells in joints plays a key role in the pathogenesis of RA in both the inflammation and bone destruction phases.