Connexin43 enhances Wnt and PGE2-dependent activation of beta-catenin in osteoblasts

摘要

Connexin43 is an important modulator of many signaling pathways in bone. beta-Catenin, a key regulator of the osteoblast differentiation and function, is among the pathways downstream of connexin43-dependent intercellular communication. There are striking overlaps between the functions of these two proteins in bone cells. However, differential effects of connexin43 on beta-catenin activity have been reported. Here, we examined how connexin43 influenced both Wnt-dependent and Wnt-independent activation of beta-catenin in osteoblasts in vitro. Our data show that loss of connexin43 in primary osteoblasts or connexin43 overexpression in UMR106 cells regulated active beta-catenin and phospho-Akt levels, with loss of connexin43 inhibiting and connexin43 overexpression increasing the levels of active beta-catenin and phospho-Akt. Increasing connexin43 expression synergistically enhanced Wnt3a-dependent activation of beta-catenin protein and beta-catenin transcriptional activity, as well as Wnt-independent activation of beta-catenin by prostaglandin E2 (PGE2). Finally, we show that the activation of beta-catenin by PGE2 required signaling through the phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase 3 beta (GSK3 beta) pathway, as the PI3K inhibitor, LY-294002, disrupted the synergy between connexin43 and PGE2. These data show that connexin43 regulates Akt and beta-catenin activity and synergistically enhances both Wnt-dependent and Wnt-independent beta-catenin signaling in osteoblasts.