Bone integrity is maintained through the coordinated action of bone resorption by osteoclasts and bone formation by osteoblasts. RANKL (receptor activator of nuclear factor kappaB (NF-kappaB) ligand) is a key factor for differentiation and activation of osteoclasts. Chronic inflammation and cancer metastasis to bone induce excessive bone resorption primarily by enhancing production of RANKL. RANKL binds to its receptor RANK (receptor activator of NF-kappaB) and initiates intercellular signaling by recruiting intercellular adaptor TRAF6 (tumor necrosis factor receptor-associated factor 6). RANKL/RANK/TRAF6-mediated signaling leads to activation of transcription factor NF-kappaB, mitogen-activated kinases JNK and p38, oncogene product c-Src and transcription factor c-Fos expression, which are important for osteoclastogenesis. However, the link between RANK/TRAF6 and the downstream effectors has not been identified. We have previously demonstrated that TAK1 (transforming growth factor beta activated kinase), a member of MAPKKK (mitogen-activated kinase kinase kinase), plays essential roles in proinflammatory signaling and cell differentiation. Recently, we have found that RANKL induces endogenous association of TAK1 and TAB2 (TAK1 binding protein 2) with RANK/TRAF6. Therefore, we hypothesize that TAK1 and TAB2 also play essential roles in RANKL signaling pathway. In this exploratory/developmental proposal, we will determine the roles of TAK1/TAB2 in RANKL-dependent signaling pathways and obtain data to develop in vivo model to further verify the specific roles of TAK1/TAB2 in osteoclastogenesis.
Our specific Aims are: 1) To determine the roles of TAK1/TAB2 in RANKL-induced NF-kappaB, JNK, p38 and c-Src activation, c-Fos induction and osteoclastogenesis: 2) To design and create mutant TAK1 and TAB2 proteins that lack the ability to transmit the RANKL-dependent signaling but are intact in mediating other signaling pathways. We will plan to use those mutants to demonstrate functional roles of the RANK/TRAF6/TAB2/TAK1 signaling in osteoclastogenesis in the future study. These studies will advance the understanding of the molecular mechanisms underlying the osteoclastogenesis and may offer novel therapeutic targets for bone diseases caused by excessive osteoclastogenesis.
