PLCγ2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2

Excessive bone loss in arthritic diseases is mostly due to abnormal activation of the immune system leading to stimulation of osteoclasts. While phospholipase C gamma (PLC gamma) isoforms are known modulators of T and B lymphocyte-mediated immune responses, we found that blockade of PLC gamma enzymatic activity also blocks early osteoclast development and function. Importantly, targeted deletion of Plcg2 in mice led to an osteopetrotic phenotype. PLC gamma 2, independent of PLC gamma 1, was required for receptor activator of NF-kappa B ligand-induced (RANKL-induced) osteoclastogenesis by differentially regulating nuclear factor of activated T cells cl (NFATcl), activator protein-1 (AP1), and NF-kappa B. Specifically, we show that NFATcl upregulation is dependent on RANKL-mediated phosphorylation of PLC gamma 2 downstream of Dap12/Fc receptor gamma (Dap12/FcR gamma) receptors and is blocked by the PLC gamma inhibitor U73122. In contrast, activation of JNK and NF-kappa B was not affected by U73122 or Dap12/FcR gamma deletion. Interestingly, we found that in osteoclasts, PLC gamma 2 formed a complex with the regulatory adapter molecule GAB2, was required for GAB2 phosphorylation, and modulated GAB2 recruitment to RANK. Thus, PLC gamma 2 mediates RANKL-induced osteoclastogenesis and is a potential candidate for antiresorptive therapy.