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    Important roles of PI3K{gamma} in osteoclastogenesis and bone homeostasis

    Proc Natl Acad Sci U S A. 2010 Jul 2. [Epub ahead of print]

    The authors examined mice deficient in the G protein-coupled receptor-regulated PI3Kgamma, which is abundantly expressed in myeloid cells. They find that these mice had a bone phenotype, which was characterized by high bone mass due to a defect in osteoclastogenesis.

    Authors: Kang H, Chang W, Hurley M, et. al

    G protein-coupled receptor-regulated PI3Kgamma 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 PI3Kgamma-deficient mouse line and found that PI3Kgamma-deficient mice had high bone mass. Our analyses further revealed that PI3Kgamma deficiency did not affect bone formation because no significant changes in osteoblast number and bone formation rate were observed. Instead, the lack of PI3Kgamma 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 PI3Kgamma regulates bone homeostasis by modulating osteoclastogenesis. Our study also suggests that inhibition of PI3Kgamma, which is being considered as a potential therapeutic strategy for treating chronic inflammatory disorders, may result in an increase in bone mass.

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