A calcium-induced signaling cascade leading to osteogenic differentiation of human bone marrow-derived mesenchymal stromal cells

A.M.C. Barradas, H.A.M. Fernandes, N. Groen, Y.C. Chai, J. Schrooten, J. van de Peppel, J.P.T.M. van Leeuwen, Clemens van Blitterswijk, Jan de Boer

Research output: Contribution to journalArticleAcademicpeer-review

246 Citations (Scopus)

Abstract

The response of osteoprogenitors to calcium (Ca2+) 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 Ca2+ released from these ceramic materials influences cells in situ. Here, we have created an in vitro environment with high extracellular Ca2+ concentration and investigated the response of human bone marrow-derived mesenchymal stromal cells (hMSCs) to it. Ca2+ 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 6 h and pharmaceutical interference with a number of proteins involved in Ca2+ 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 Ca2+ and BMP-2 expression. MEK1/2 activity is essential for the effect of Ca2+ and using microarray analysis, we have identified c-Fos as an early Ca2+ response gene. We have demonstrated that hMSC osteogenesis can be induced via extracellular Ca2+, a simple and economic way of priming hMSCs for bone tissue engineering applications.
Original languageEnglish
Pages (from-to)3205-3215
Number of pages11
JournalBiomaterials
Volume33
Issue number11
DOIs
Publication statusPublished - 2012

Keywords

  • Calcium phosphate
  • Bone morphogenetic protein
  • IR-80575
  • Osteogenesis
  • METIS-286589
  • Stem cell

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