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Molecular and Cellular Biology, December 2008, p. 7182-7198, Vol. 28, No. 23
0270-7306/08/$08.00+0 doi:10.1128/MCB.00920-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
The p85
Subunit of Class IA Phosphatidylinositol 3-Kinase Regulates the Expression of Multiple Genes Involved in Osteoclast Maturation and Migration
Veerendra Munugalavadla,1,4,
Sasidhar Vemula,1,4
Emily Catherine Sims,1,4
Subha Krishnan,1,4
Shi Chen,1,4
Jincheng Yan,1,4
Huijie Li,1,4
Paul J. Niziolek,2,
Clifford Takemoto,3
Alexander G. Robling,2
Feng-Chun Yang,1,4 and
Reuben Kapur1,4*
Department of Pediatrics,4 Department of Biochemistry and Molecular Biology,1 Departments of Anatomy and Cell Biology, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana,2 Division of Pediatric Hematology, The Johns Hopkins University, Baltimore, Maryland3
Received 9 June 2008/ Returned for modification 6 August 2008/ Accepted 11 September 2008
Intracellular signals involved in the maturation and function of osteoclasts are poorly understood. Here, we demonstrate that osteoclasts express multiple regulatory subunits of class IA phosphatidylinositol 3-kinase (PI3-K) although the expression of the full-length form of p85
is most abundant. In vivo, deficiency of p85 results in a significantly greater number of trabeculae and significantly lower spacing between trabeculae as well as increased bone mass in both males and females compared to their sex-matched wild-type controls. Consistently, p85–/– osteoclast progenitors show impaired growth and differentiation, which is associated with reduced activation of Akt and mitogen-activated protein kinase extracellular signal-regulated kinase 1 (Erk1)/Erk2 in vitro. Furthermore, a significant reduction in the ability of p85–/– osteoclasts to adhere to as well as to migrate via integrin vβ3 was observed, which was associated with reduced bone resorption. Microarray as well as quantitative real-time PCR analysis of p85–/– osteoclasts revealed a significant reduction in the expression of several genes associated with the maturation and migration of osteoclasts, including microphathalmia-associated transcription factor, tartrate-resistant acid phosphatase, cathepsin K, and β3 integrin. Restoring the expression of the full-length form of p85 but not the version with a deletion of the Src homology-3 domain restored the maturation of p85–/– osteoclasts to wild-type levels. These results highlight the importance of the full-length version of the p85 subunit of class IA PI3-K in controlling multiple aspects of osteoclast functions.
* Corresponding author. Mailing address: Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Cancer Research Institute, 1044 W. Walnut Street, Room 425, Indianapolis, IN 46202. Phone: (317) 274-4658. Fax: (317) 274-8679. E-mail: rkapur{at}iupui.edu
Published ahead of print on 22 September 2008.
Present address: Cancer Signaling and Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA.
Present address: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN.
Molecular and Cellular Biology, December 2008, p. 7182-7198, Vol. 28, No. 23
0270-7306/08/$08.00+0 doi:10.1128/MCB.00920-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
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