title: PS1/γ-Secretase-Mediated Cadherin Cleavage Inducesβ-Catenin Nuclear Translocation and Osteogenic Differentiation of Human Bone Marrow Stromal Cells.
abstract: Bone marrow stromal cells (BMSCs) are considered a promising tool for bone bioengineering. However, the mechanisms controlling osteoblastic commitment are still unclear. Osteogenic differentiation of BMSCs requires the activation ofβ-catenin signaling, classically known to be regulated by the canonical Wnt pathway. However, BMSCs treatment with canonical Wntsin vitrodoes not always result in osteogenic differentiation and evidence indicates that a more complex signaling pathway, involving cadherins, would be required to induceβ-catenin signaling in these cells. Here we showed that Wnt3a alone did not induce TCF activation in BMSCs, maintaining the cells at a proliferative state. On the other hand, we verified that, upon BMSCs osteoinduction with dexamethasone, cadherins were cleaved by the PS1/γ-secretase complex at the plasma membrane, and this event was associated with an enhancedβ-catenin translocation to the nucleus and signaling. When PS1/γ-secretase activity was inhibited, the osteogenic process was impaired. Altogether, we provide evidence that PS1/γ-secretase-mediated cadherin cleavage has as an important role in controllingβ-catenin signaling during the onset of BMSCs osteogenic differentiation, as part of a complex signaling pathway responsible for cell fate decision. A comprehensive map of these pathways might contribute to the development of strategies to improve bone repair.
authors.affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Danielle C
authors.identifier: 0000-0002-6850-2061
authors.initials: DC
authors.lastname: Bonfim
authors.affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Rhayra B
authors.initials: RB
authors.lastname: Dias
authors.affiliation: Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Institute of Medical Biochemistry, National Institute of Cancer, Rio de Janeiro, RJ, Brazil.
authors.forename: Anneliese
authors.initials: A
authors.lastname: Fortuna-Costa
authors.affiliation: Molecular Carcinogenesis Program, National Institute of Cancer, Rio de Janeiro, RJ, Brazil; Evandro Chagas Clinical Research Institute, Oswaldo Cruz Institute (FIOCRUZ), Rio de Janeiro, RJ, Brazil.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Chicaybam
authors.affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Daiana V
authors.initials: DV
authors.lastname: Lopes
authors.affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Hélio S
authors.initials: HS
authors.lastname: Dutra
authors.affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Radovan
authors.initials: R
authors.lastname: Borojevic
authors.affiliation: Molecular Carcinogenesis Program, National Institute of Cancer, Rio de Janeiro, RJ, Brazil.
authors.forename: Martin
authors.initials: M
authors.lastname: Bonamino
authors.affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mermelstein
authors.affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Maria Isabel D
authors.identifier: 0000-0003-3432-8453
authors.initials: MI
authors.lastname: Rossi