Aditi GuptaSaimai ChatreeAtum M. BuoMegan C. MoorerJoseph P. StainsUniversity of Maryland School of MedicineMahidol University2020-01-272020-01-272019-09-01Pflugers Archiv European Journal of Physiology. Vol.471, No.9 (2019), 1235-124314322013003167682-s2.0-85067999840https://repository.li.mahidol.ac.th/handle/20.500.14594/50087© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Connexin43 is an important modulator of many signaling pathways in bone. β-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 β-catenin activity have been reported. Here, we examined how connexin43 influenced both Wnt-dependent and Wnt-independent activation of β-catenin in osteoblasts in vitro. Our data show that loss of connexin43 in primary osteoblasts or connexin43 overexpression in UMR106 cells regulated active β-catenin and phospho-Akt levels, with loss of connexin43 inhibiting and connexin43 overexpression increasing the levels of active β-catenin and phospho-Akt. Increasing connexin43 expression synergistically enhanced Wnt3a-dependent activation of β-catenin protein and β-catenin transcriptional activity, as well as Wnt-independent activation of β-catenin by prostaglandin E2 (PGE2). Finally, we show that the activation of β-catenin by PGE2 required signaling through the phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase 3 beta (GSK3β) pathway, as the PI3K inhibitor, LY-294002, disrupted the synergy between connexin43 and PGE2. These data show that connexin43 regulates Akt and β-catenin activity and synergistically enhances both Wnt-dependent and Wnt-independent β-catenin signaling in osteoblasts.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyMedicineArticleSCOPUS10.1007/s00424-019-02295-y