Direct activation of PI3K in osteoblasts and osteocytes strengthens murine bone through sex-specific actions on cortical surfaces.

This article investigates the effects of direct activation of phosphoinositide 3-kinase alpha (PI3Kα) in osteoblasts and osteocytes on bone structure and strength in mice, using a gain-of-function Pik3ca^H1047R mutation driven by dentin matrix protein-1 Cre (Dmp1Cre). The study found that this targeted PI3Kα activation increased cortical bone thickness and strength in both male and female mice, with females exhibiting additional periosteal expansion over time, resulting in further bone strengthening. Unlike models with PTEN deletion (which removes a PI3K inhibitor), the bone formed here was well-organized lamellar bone without increased intracortical remodeling or porosity. These findings suggest that direct PI3Kα activation in late osteoblast lineage cells promotes controlled lamellar bone formation and may represent a more favorable target for enhancing bone strength compared to PTEN loss.