The p85α Subunit of Class I_A 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 p85α is most abundant. In vivo, deficiency of p85α 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, p85α^−/− 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 p85α^−/− osteoclasts to adhere to as well as to migrate via integrin αvβ3 was observed, which was associated with reduced bone resorption. Microarray as well as quantitative real-time PCR analysis of p85α^−/− 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 p85α but not the version with a deletion of the Src homology-3 domain restored the maturation of p85α^−/− osteoclasts to wild-type levels. These results highlight the importance of the full-length version of the p85α subunit of class I_A PI3-K in controlling multiple aspects of osteoclast functions.

ACKNOWLEDGMENTS

We thank Marilyn Wales for assistance in manuscript preparation.

We have no conflict of interests to declare.

This work was supported by NIH grants R01 HL075816 and R01 HL077177 to R.K.