title: Class I PI-3-Kinase Signaling Is Critical for Bone Formation Through Regulation of SMAD1 Activity in Osteoblasts.
abstract: Bone formation and homeostasis is carried out by osteoblasts, whose differentiation and activity are regulated by osteogenic signaling networks. A central mediator of these inputs is the lipid kinase phosphatidylinositol 3-kinase (PI3K). However, at present, there are no data on the specific role of distinct class IA PI3K isoforms in bone biology. Here, we performed osteoblast-specific deletion in mice to show that both p110α and p110β isoforms are required for survival and differentiation and function of osteoblasts and thereby control bone formation and postnatal homeostasis. Impaired osteogenesis arises from increased GSK3 activity and a depletion of SMAD1 protein levels in PI3K-deficient osteoblasts. Accordingly, pharmacological inhibition of GSK3 activity or ectopic expression of SMAD1 or SMAD5 normalizes bone morphogenetic protein (BMP) transduction and osteoblast differentiation. Together, these results identify the PI3K-GSK3-SMAD1 axis as a central node integrating multiple signaling networks that govern bone formation and homeostasis. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Departament de Ciències Fisiològiques II, Universitat de Barcelona, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Gámez
authors.affiliation: Departament de Ciències Fisiològiques II, Universitat de Barcelona, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Edgardo
authors.initials: E
authors.lastname: Rodríguez-Carballo
authors.affiliation: Vascular Signaling Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Graupera
authors.affiliation: Departament de Ciències Fisiològiques II, Universitat de Barcelona, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Rosa
authors.affiliation: Departament de Ciències Fisiològiques II, Universitat de Barcelona, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Ventura
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001851:Bone Diseases, Metabolic / Q000201:enzymology / Q000473:pathology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D017353:Gene Deletion; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006706:Homeostasis; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis; D010641:Phenotype; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D019485:Bone Morphogenetic Proteins; D051898:Smad1 Protein; D058539:Phosphatidylinositol 3-Kinase; D038362:Glycogen Synthase Kinase 3
keywords: BMP; BONE DEVELOPMENT; OSTEOBLAST; PI3K; SMAD