Funder(s): NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases
In this study, we pursue our research on the molecular mechanisms of the differentiation of osteoclasts and bone resorption. The understanding osteoclast (OC) differentiation and activity has been revolutionized by the discovery that (1) the activation of RANK by RANK ligand is absolutely required for osteoclast formation and activity, and (2) stimulation of myelomonocytic precursors with M-CSF and RANK ligand is sufficient to induce the formation of OCs. Less publicized, but in our eyes important as well, have been the findings that the Cbl family of proteins is both involved in osteoclast biology and in the down-regulation and/or signaling activity of RANK and M-CSF, as well as other activated tyrosine kinase receptors. Because of the central importance, on the one hand, of RANK and M-CSF in osteoclast biology, particularly differentiation, and, on the other hand, of the Cbl family of proteins in the regulation of signaling and degradation of these receptors, including recent and exciting findings from our group we plan to focus our efforts on the functional role of Cbl-b in the regulation of OC differentiation and bone resorption by RANK and the M-CSF receptor, c-Fms.
We have recently observed that both c-Cbl and Cbl-b knockouts have osteoclastic phenotypes, but very different ones, with only the absence of Cbl-b resulting in a several-fold increase in the expression of RANK on the OC surface, increased OC differentiation and bone resorption and osteopenia. We are therefore working to identify the molecular mechanisms by which Cbl-b regulates signaling by RANK and c-Fms and OC biology. Consequently, the aims of this study are to (1) further analyze the phenotype of the Cbl-b knockout at the bone, osteoclast, and molecular levels (focusing particularly on NKL- and M-CSF-induced signaling); (2) analyze in vitro the molecular mechanisms involved, mimicking, or rescuing the osteoclast phenotype in single KO cells and identifying the domains and signaling pathways responsible for the Cbl-b phenotype; and (3) express the mutated Cbl-b proteins that rescue/mimic the Cbl-b phenotype in vitro in single knockout transgenic mice. This work ] will increase our understanding of the regulation of bone resorption, potentially identifying novel targets for therapeutic intervention to control bone loss related to osteoporosis, arthritis, bone metastasis, and periodontal diseases.