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,
p85
α
−/−
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
α
−/−
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
p85
α
−/−
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
p85
α
−/−
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.
