Research Abstract:
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 PLCγ2 as central mediator of RANKL-induced osteoclastogenesis, independent of PLCγ1. 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 PLCγ2 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 PLCγ2 required for OC differentiation and understand the mechanism leading to PLCγ2 activation, but not PLCγ1, in the bone resorbing cells; 2) examine the interaction of PLCγ2 with element of the OC cytoskeleton and the αvβ3 integrin during bone resorption; and 3) considering the importance of PLCγ2 in regulation of B cell mediated immune responses and osteoclastogenesis, determine the relative PLCγ2-dependent contribution of B and T cells in the development of inflammation and bone erosion in rheumatoid arthritis and study the role of PLCγ2 in OC activation and bone erosion in vivo, studies which may unveil novel OC regulatory mechanisms and provide the basis for new antiresorptive therapies.
Selected Publications:
Mao D, Epple H, Uthgenannt B, Novack DV, Faccio R. PLCgamma2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2. JCI 2006 (in press).
Faccio R, Fujikawa K, Teitelbaum SL, Ross FP, Swat W. Regulation of osteoclast function and bone density by Vav3. Nat Med 2005 11:284-290.
Faccio R, Novack DV, Zallone A, Ross FP, Teitelbaum SL. Dynamic changes in the osteoclast cytoskeleton in response to growth factors and cell attachment are controlled by beta(3) integrin. J Cell Biol 2003 162:499-509.
Faccio R, Takeshita S, Zallone A, Ross FP, Teitelbaum SL. c-Fms and the alpha(v)beta(3) integrin collaborate during osteoclast differentiation. J Clin Invest 2003 111:749-758.
Faccio R, Zou W, Colaianni G, Teitelbaum SL, Ross FP. High dose M-CSF partially rescues the Dap12-/- osteoclast phenotype. J Cell Biochem 2003 90: 871-883.
Last Updated: 11/18/2009 |