Abstract
Bone destruction associated with rheumatoid arthritis (RA) is caused by the enhanced activation of osteoclasts, which are terminally differentiated cells of monocyte/macrophage lineage that resorb bone matrix. Accumulating evidence lends support to the theory that interleukin (IL)-17-producing helper T (Th17) cells induce the expression of receptor activator of nuclear factor-κB ligand (RANKL) in synovial cells, which in turn stimulates the differentiation and activation of osteoclasts together with inflammatory cytokines. Thus, a better understanding of the mechanism of Th17 induction is important for the development of effective therapeutic strategies against RA. Our study indicates that cathepsin K, which was thought to be an osteoclast-specific enzyme, also functions as a regulator of TLR9 signaling in dendritic cells, and thus is a potential therapeutic target for the control of Th17-mediated autoimmune inflammation. Furthermore, we have explored the transcriptional program of Th17 development, and discovered that the transcriptional regulator IκBξ is essential for the development of Th17 cells. These findings comprise an important advance in our understanding of the mechanism of Th17 development, providing molecular basis for novel effective therapeutic approaches.
