Noncanonical Wnt signaling through G protein-linked PKC delta activation promotes bone formation

Wnt signaling regulates a variety of developmental processes in animals. Although the beta-catenin-dependent (canonical) pathway is known to control cell fate, a similar role for noncanonical Wnt signaling has not been established in mammals. Moreover, the intracellular cascades for noncanonical Wnt signaling remain to be elucidated. Here, we delineate a pathway in which Wnt3a signals through the G alpha(q/11) subunits of G proteins to activate phosphatidylinositol signaling and PKC delta in the murine ST2 cells. G alpha(q/11)-PKC delta signaling is required for Wnt3a-induced osteoblastogenesis in these cells, and PKC delta homozygous mutant mice exhibit a deficit in embryonic bone formation. Furthermore, Wnt7b, expressed by osteogenic cells in vivo, induces osteoblast differentiation in vitro via the PKC delta-mediated pathway; ablation of Wnt7b in skeletal progenitors results in less bone in the mouse embryo. Together, these results reveal a Wnt-dependent osteogenic mechanism, and they provide a potential target pathway for designing therapeutics to promote bone formation.