title: Bmp Induces Osteoblast Differentiation through both Smad4 and mTORC1 Signaling.
abstract: The bone morphogenetic protein (Bmp) family of secreted molecules has been extensively studied in the context of osteoblast differentiation. However, the intracellular signaling cascades that mediate the osteoblastogenic function of Bmp have not been fully elucidated. By profiling mRNA expression in the bone marrow mesenchymal progenitor cell line ST2, we discover that BMP2 induces not only genes commonly associated with ossification and mineralization but also genes important for general protein synthesis. We define the two groups of genes as mineralization related versus protein anabolism signatures of osteoblasts. Although it induces the expression of several Wnt genes, BMP2 activates the osteogenic program largely independently of de novo Wnt secretion. Remarkably, although Smad4 is necessary for the activation of the mineralization-related genes, it is dispensable for BMP2 to induce the protein anabolism signature, which instead critically depends on the transcription factor Atf4. Upstream of Atf4, BMP2 activates mTORC1 to stimulate protein synthesis, resulting in an endoplasmic reticulum stress response mediated by Perk. Thus, Bmp signaling induces osteoblast differentiation through both Smad4- and mTORC1-dependent mechanisms.
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Karner
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Seung-Yon
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA flong@wustl.edu.|Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Fanxin
authors.initials: F
authors.lastname: Long
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D002113:Calcification, Physiologic / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051901:Smad4 Protein / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D051153:Wnt Proteins / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051701:Activating Transcription Factor 4; D055396:Bone Morphogenetic Protein 2; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D016315:Proto-Oncogene Proteins c-abl; D051901:Smad4 Protein; D058570:TOR Serine-Threonine Kinases; D051153:Wnt Proteins; D019892:eIF-2 Kinase
keywords: Atf4; ER stress; Perk; Smad4; bone morphogenic proteins (BMPs); mTOR; mTORC1; mineralization; osteoblast; protein anabolism