Identifying common signaling pathways to bone and immune system may lead to better therapeutic approaches in diseases such as inflammatory arthritis. In this context, PLCgamma2 seems to be a promising target. PLCgamma2 modulates bone homeostasis by affecting osteoclast recruitment and function. Via its catalytic activity and the adapter domains, PLCgamma2 controls RANKL and alphavbeta3 integrin-dependent signaling pathways in the resorbing cell. Thus, mice lacking PLCgamma2 are osteopetrotic. PLCgamma2 also regulates neutrophil degranulation after beta2 integrin-dependent attachment. Indeed PLCgamma2(-/-) mice are protected from K/BxN serum transfer arthritis, which is known to require neutrophil activation. These studies position PLCgamma2 as a critical regulator of the cellular and molecular mechanisms occurring in bone and immune cells during autoimmune inflammation.