Lipid Raft Associated Signaling in Regulation of Osteoclast Activation in Inflammatory Arthritis

The role of RANKL in promoting the differentiation of osteoclasts has been extensively characterized. RANKL activates TRAF6 signaling pathways, which are indispensable for the induction and activation of osteoclastogenesis. In previous study, we have demonstrated that in addition to triggering apoptosis, TRAIL induces osteoclast differentiation, and TRAIL induced osteoclast differentiation via a TRAF-6-dependent signaling pathway (PLoS One. 2012;7(6):e38048.). Interestingly, our results also demonstrated that TRAIL suppressed osteoclastic differentiation induced by RANKL plus M-CSF, suggesting that TRAIL may play a role in regulating osteoclast differentiation in osteoimmunology. The signaling pathways regulated by TRAIL in osteoclast differentiation is still not clear. Our preliminary results demonstrated that RANK-mediated signaling and osteoclast function are critically dependent on the expression and integrity of raft membrane microdomains, and TRAIL regulated RANKL-induced osteoclastogenesis via targeting at lipid raft associated signaling. Furthermore, in collagen-induced arthritis rat animal model, treatment with TRAIL not only the improved the bone density and inhibited bone erosion, but also reduced the joint swelling and inflammation. For further exploring the signaling pathways determine the osteoclast differentiation and inflammation; in this project, we will focus on the following aims: 1.To investigate lipid raft assembly in TRAL-induced regulation of osteoclast differentiation and inflammation. 2. To define the key regulators in lipid raft associated signaling which TRAIL targets in regulation of RANKL signaling in osteoclast differentiation via cDNA and micro-RNA microarray screening. 3. For further investigate the role of TRAIL and lipid raft associated signaling pathways in immune-mediated osteoclastogenesis in inflammatory disease, we will study the therapeutic role of TRAIL in bone erosion and joint inflammation in autoimmune arthritis mice model. The novel function of TRAIL in osteoclastogenesis and inflammatory arthritis indicates a therapeutic role of TRAIL in inflammatory arthritis and osteoimmunology, and will be helpful in developing better strategies for treating inflammation-induced bone resorption in the future.