PTEN and adherens junctions during osteoblastogenesis

N‐cadherin containing cell‐cell junctions form synchronously with osteoblast differentiation during bone formation in vivo. PTEN, a principal regulator of phosphatidylinositol 3‐kinase (PI3‐K) signaling, is upregulated in the same population of developing osteoblasts, implying a tight coupling of osteoblast differentiation, adherens junction assembly and phosphatidylinositol 3‐kinase (PI3‐K) signaling. We hypothesized a direct causal relationship between PI3‐K signaling, adherens junction formation and osteoblast differentiation. To examine this relationship we evaluated 1) PI3‐K signaling as a function of assembly and dissolution of adherens junctions and 2) the osteoblast differentiation as a function of PI3‐K signaling and assembly of cell‐cell contacts. We found that PI3‐K signaling was induced by the formation of and inhibited by the dissolution of intercellular contacts, and this was linked to the expression of genes related to osteoblast differentiation. Conditional ablation of the PTEN gene in vivo caused a dramatic increase in osteoblast differentiation and bone formation. In addition, osteoblasts developed precociously indicating dissociation from normal physiological constraints. These data indicate that osteoblast development is strictly regulated by PI3‐K signaling and that adherens junctions and PTEN titrate PI3‐K signaling during osteoblastogenesis.