title: The p85alpha subunit of class IA phosphatidylinositol 3-kinase regulates the expression of multiple genes involved in osteoclast maturation and migration.
abstract: Intracellular signals involved in the maturation and function of osteoclasts are poorly understood. Here, we demonstrate that osteoclasts express multiple regulatory subunits of class I(A) phosphatidylinositol 3-kinase (PI3-K) although the expression of the full-length form of p85alpha is most abundant. In vivo, deficiency of p85alpha 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, p85alpha(-/-) 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 p85alpha(-/-) osteoclasts to adhere to as well as to migrate via integrin alphavbeta3 was observed, which was associated with reduced bone resorption. Microarray as well as quantitative real-time PCR analysis of p85alpha(-/-) 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 beta3 integrin. Restoring the expression of the full-length form of p85alpha but not the version with a deletion of the Src homology-3 domain restored the maturation of p85alpha(-/-) osteoclasts to wild-type levels. These results highlight the importance of the full-length version of the p85alpha subunit of class I(A) PI3-K in controlling multiple aspects of osteoclast functions.
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research,2 Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Veerendra
authors.initials: V
authors.lastname: Munugalavadla
authors.forename: Sasidhar
authors.initials: S
authors.lastname: Vemula
authors.forename: Emily Catherine
authors.initials: EC
authors.lastname: Sims
authors.forename: Subha
authors.initials: S
authors.lastname: Krishnan
authors.forename: Shi
authors.initials: S
authors.lastname: Chen
authors.forename: Jincheng
authors.initials: J
authors.lastname: Yan
authors.forename: Huijie
authors.initials: H
authors.lastname: Li
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Niziolek
authors.forename: Clifford
authors.initials: C
authors.lastname: Takemoto
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Robling
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
mesh_terms: D000818:Animals; D001862:Bone Resorption; D002448:Cell Adhesion; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology* / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000502:physiology*; D021122:Protein Subunits
chemical_list: D021122:Protein Subunits; D019869:Phosphatidylinositol 3-Kinases