Regulation of RANKL signaling in arthritic bone destruction
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KeywordsRheumatoid Arthritis FK506 Bone Destruction Osteoclast Differentiation Tumor Necrosis Factor Family
Formation of osteoclasts is induced by a tumor necrosis factor family cytokine, RANKL (receptor activator of NF-κB ligand). To maintain the normal bone homeostasis and to prevent the pathological bone resorption, RANKL signaling must be strictly kept in control.
During the course of our study on the bone loss in rheumatoid arthritis (RA), we found that RANKL expressed on synovial fibroblasts is responsible for osteoclastogenesis from synoviocytes. However, it has been also reported that RANKL-expressing T cells are involved in osteoclastogenesis in RA. We then focused on the regulation of osteoclast differentiation by T cells. Using mice lacking a receptor component for IFN-γ, we revealed that T-cell production of IFN-γ strongly suppresses osteoclastogenesis by interfering with the RANKL signaling pathway . We have shed light on a new biological function of IFN-γ, which is to protect against calcified tissue destruction upon T-cell activation, demonstrating that activated T cells not only positively regulate, but also negatively affect osteoclastogenesis.
To explore the molecular targets for suppressing bone destruction in RA, we performed a genome-wide screening of RANKL-inducible genes. We found that RANKL induces IFN-β, a critical cytokine for antiviral defense. Mice deficient in IFN-β signaling exhibited severe osteopenia accompanied by enhanced osteoclastogenesis, suggesting that IFN-β is essential for normal bone remodeling by suppressing excessive osteoclast differentiation . In addition, we revealed beneficial effects of IFN-β in animal models of pathological bone resorption.
We have recently identified that the transcription factor NFATc1 is specifically induced by RANKL . We demonstrate that NFATc1-deficient embryonic stem cells fail to differentiate into osteoclasts in response to RANKL stimulation, and the ectopic expression of NFATc1 causes the precursor cells to undergo efficient differentiation without RANKL signaling. Thus, NFATc1 may be a master switch regulator for the terminal differentiation of osteoclasts, functioning downstream of RANKL signaling. The activation of NFATc1 by RANKL is regulated by calcium-dependent phosphatase, calcineurin, and calcineurin inhibitors such as FK506 and cyclosporin A strongly suppress osteoclastogenesis. The possibility of NFATc1 as a therapeutic target of bone destruction in RA will be discussed.