Important roles of PI3Kγ in osteoclastogenesis and bone homeostasis

G protein-coupled receptor-regulated PI3K gamma is abundantly expressed in myeloid cells and has been implicated as a promising drug target to treat various inflammatory diseases. However, its role in bone homeostasis has not been investigated, despite the fact that osteoclasts are derived from myeloid lineage. We therefore carried out thorough bone phenotypic characterization of a PI3K gamma-deficient mouse line and found that PI3K gamma-deficient mice had high bone mass. Our analyses further revealed that PI3K gamma deficiency did not affect bone formation because no significant changes in osteoblast number and bone formation rate were observed. Instead, the lack of PI3K gamma was associated with decreased bone resorption, as evidenced by decreased osteoclast number in vivo and impaired osteoclast formation in vitro. The decreased osteoclast formation was accompanied by down-regulated expression of osteoclastogenic genes, compromised chemokine receptor signaling, and an increase in apoptosis during osteoclast differentiation. Together, these data suggest that PI3K gamma regulates bone homeostasis by modulating osteoclastogenesis. Our study also suggests that inhibition of PI3K gamma, which is being considered as a potential therapeutic strategy for treating chronic inflammatory disorders, may result in an increase in bone mass.