Important roles of PI3Kgamma in osteoclastogenesis and bone homeostasis.
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.
Kang
Heeseog
H
Vascular Biology and Therapeutics Program and Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Chang
Woochul
W
Hurley
Marja
M
Vignery
Agnès
A
Wu
Dianqing
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D002452:Cell Count; D018925:Chemokines / Q000494:pharmacology; D058544:Class Ib Phosphatidylinositol 3-Kinase; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D017353:Gene Deletion; D006706:Homeostasis / Q000187:drug effects; D007527:Isoenzymes / Q000172:deficiency / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010012:Osteogenesis / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D018925:Chemokines; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D051057:Proto-Oncogene Proteins c-akt