title: A calcium-induced signaling cascade leading to osteogenic differentiation of human bone marrow-derived mesenchymal stromal cells.
abstract: The response of osteoprogenitors to calcium (Ca(2+)) is of primary interest for both normal bone homeostasis and the clinical field of bone regeneration. The latter makes use of calcium phosphate-based bone void fillers to heal bone defects, but it is currently not known how Ca(2+) released from these ceramic materials influences cells in situ. Here, we have created an in vitro environment with high extracellular Ca(2+) concentration and investigated the response of human bone marrow-derived mesenchymal stromal cells (hMSCs) to it. Ca(2+) enhanced proliferation and morphological changes in hMSCs. Moreover, the expression of osteogenic genes is highly increased. A 3-fold up-regulation of BMP-2 is observed after only 6h and pharmaceutical interference with a number of proteins involved in Ca(2+) sensing showed that not the calcium sensing receptor, but rather type L voltage-gated calcium channels are involved in mediating the signaling pathway between extracellular Ca(2+) and BMP-2 expression. MEK1/2 activity is essential for the effect of Ca(2+) and using microarray analysis, we have identified c-Fos as an early Ca(2+) response gene. We have demonstrated that hMSC osteogenesis can be induced via extracellular Ca(2+), a simple and economic way of priming hMSCs for bone tissue engineering applications.
authors.affiliation: Department of Tissue Regeneration, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Drienerlolaan 5, 7522 NB Enschede, The Netherlands. margarida.barradas@gmail.com
authors.forename: Ana M C
authors.initials: AM
authors.lastname: Barradas
authors.forename: Hugo A M
authors.initials: HA
authors.lastname: Fernandes
authors.forename: Nathalie
authors.initials: N
authors.lastname: Groen
authors.forename: Yoke Chin
authors.initials: YC
authors.lastname: Chai
authors.forename: Jan
authors.initials: J
authors.lastname: Schrooten
authors.forename: Jeroen
authors.initials: J
authors.lastname: van de Peppel
authors.forename: Johannes P T M
authors.initials: JP
authors.lastname: van Leeuwen
authors.forename: Clemens A
authors.initials: CA
authors.lastname: van Blitterswijk
authors.forename: Jan
authors.initials: J
authors.lastname: de Boer
mesh_terms: D002118:Calcium / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D010006:Osteoblasts / Q000166:cytology* / Q000502:physiology*; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D023822:Tissue Engineering / Q000379:methods
chemical_list: D002118:Calcium