한빛사논문
- 조회3,910
Abstract
Heeseog Kanga, Woochul Changa, Marja Hurleyb, Agnes Vigneryc, and Dianqing Wua,1
aVascular Biology and Therapeutics Program and Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;
bDepartment of Medicine, University of Connecticut Health Center, Farmington, CT 06030; and
cDepartment of Medicine and Cell Biology, Yale University School of Medicine, New Haven, CT 06520
Edited by Melvin I. Simon, California Institute of Technology, Pasadena, CA, and approved June 8, 2010 (received for review February 12, 2010)
Abstract
G protein-coupled receptor-regulated PI3Kγ 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 PI3Kγ-deficient mouse line and found that PI3Kγ-deficient mice had high bone mass. Our analyses further revealed that PI3Kγ deficiency did not affect bone formation because no significant changes in osteoblast number and bone formation rate were observed. Instead, the lack of PI3Kγ 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 PI3Kγ regulates bone homeostasis by modulating osteoclastogenesis. Our study also suggests that inhibition of PI3Kγ, which is being considered as a potential therapeutic strategy for treating chronic inflammatory disorders, may result in an increase in bone mass.
chemokine, signaling, apoptosis
Footnotes
1To whom correspondence should be addressed.
Author contributions: H.K., M.H., A.V., and D.W. designed research; H.K., W.C., and D.W. performed research; M.H. and A.V. contributed new reagents/analytic tools; H.K., W.C., M.H., A.V., and D.W. analyzed data; and H.K., W.C., M.H., A.V., and D.W. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at
www.pnas.org/lookup/suppl/doi:10.1073/pnas.1001499107/-/DCSupplemental.
논문정보
- Research article
- 2010년 07월 (BRIC 등록일 )
- 국외 연구진
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