Excessive bone loss in rheumatoid arthritis and some bone metastasis is mostly due to an abnormal activation of the immune system leading to stimulation of osteoclasts (OCs). Our goal is to discover common signaling molecules affecting the osteo-immune system and study their impact on normal and pathological bone loss. We have identified a novel role for the immunomodulatory protein PLCgamma2 as central mediator of RANKL-induced osteoclastogenesis, independent of PLCgamma1. OCs, the principal bone resorbing cells, develop from bone marrow macrophages primarily under the influence of two major regulators: M-CSF and RANKL, and less understood costimulatory factors that act via immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors on OC precursor cells. Our data indicate that targeted deletion of PLCgamma2 leads to an osteopetrotic phenotype due to defective OC recruitment and function. Thus, the interest  of my lab is to 1) identify structural domains of PLCgamma2 required for OC differentiation and understand the mechanism leading to PLCgamma2 activation, but not PLCgamma1, in the bone resorbing cells; 2) examine the interaction of PLCgamma2 with element of the OC cytoskeleton and the avß3 integrin during bone resorption and study the role of PLCgamma2 in OC activation and bone erosion in vivo; 3) considering the importance of PLCgamma2 in regulation of B cell mediated immune responses and osteoclastogenesis, determine the relative PLCgamma2-dependent contribution of B and T cells in the development of inflammation and bone erosion in rheumatoid arthritis; and 4) study the role of the of PLCgamma2 in the progression of breast cancer induced bone metastases. These studies might unveil novel OC regulatory mechanisms and provide the basis for new antiresorptive therapies in the context of inflammatory bone loss and bone cancer metastases.