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

Ana M.C. Barradas, Hugo A.M. Fernandes, Nathalie Groen, Yoke Chin Chai, Jan Schrooten, Jeroen Van de Peppel, Johannes P.T.M. Van Leeuwen, Clemens A. Van Blitterswijk, Jan De Boer

Research output: Contribution to journalArticleAcademicpeer-review

260 Citations (Scopus)

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 invitro 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.

Original languageEnglish
Pages (from-to)3205-3215
Number of pages11
JournalBiomaterials
Volume33
Issue number11
DOIs
Publication statusPublished - 1 Apr 2012
Externally publishedYes

Keywords

  • Bone morphogenetic protein
  • Calcium phosphate
  • Osteogenesis
  • Stem cell

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