Identifying common signaling pathways to bone and immune system may lead to better therapeutic approaches in diseases such as inflammatory arthritis. In this context, PLCγ2 seems to be a promising target. PLCγ2 modulates bone homeostasis by affecting osteoclast recruitment and function. Via its catalytic activity and the adapter domains, PLCγ2 controls RANKL and αvβ3 integrin-dependent signaling pathways in the resorbing cell. Thus, mice lacking PLCγ2 are osteopetrotic. PLCγ2 also regulates neutrophil degranulation after β2 integrin-dependent attachment. Indeed PLCγ2-/- mice are protected from K/BxN serum transfer arthritis, which is known to require neutrophil activation. These studies position PLCγ2 as a critical regulator of the cellular and molecular mechanisms occurring in bone and immune cells during autoimmune inflammation.