The close relationship between the bone and the immune system has been increasingly recognized, in particular during pathological conditions in which activation of both systems occurs, such as during inflammatory arthritis and breast cancer bone metastases. However, the biology regulating osteo-immune cross talk is incompletely understood and traditional pharmacotherapy for inflammatory and osteolytic diseases is often inadequate in controlling symptoms and disease progression. For these reasons, the Faccio’s Lab focuses on the identification of common molecules that can modulate the activation of immune cells as well as osteoclasts. We have recently documented the relevance of the Phospholipase C gamma 2 (PLCγ2) pathway in bone destruction and immune activation associated with inflammatory arthritis and bone metastasis. We are currently investigating the role of PLCγ2 and its downstream effectors in osteoclasts, neutrophils, dendritic cells and myeloid-derived immune suppressor cells in vitro and in vivo. Deciphering the mechanisms of PLCγ2 activation/function in bone and immune cells will likely provide promising opportunities to develop targeted therapeutic approaches for treatment of diseases characterized by pathological inflammation and bone loss.