title: cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo.
abstract: Tissue engineering of large bone defects is approached through implantation of autologous osteogenic cells, generally referred to as multipotent stromal cells or mesenchymal stem cells (MSCs). Animal-derived MSCs successfully bridge large bone defects, but models for ectopic bone formation as well as recent clinical trials demonstrate that bone formation by human MSCs (hMSCs) is inadequate. The expansion phase presents an attractive window to direct hMSCs by pharmacological manipulation, even though no profound effect on bone formation in vivo has been described so far using this approach. We report that activation of protein kinase A elicits an immediate response through induction of genes such as ID2 and FosB, followed by sustained secretion of bone-related cytokines such as BMP-2, IGF-1, and IL-11. As a consequence, PKA activation results in robust in vivo bone formation by hMSCs derived from orthopedic patients.
authors.affiliation: Department of Tissue Regeneration, Institute for Biomedical Technology, University of Twente, 7500 AE, Enschede, The Netherlands.
authors.forename: Ramakrishnaiah
authors.initials: R
authors.lastname: Siddappa
authors.forename: Anton
authors.initials: A
authors.lastname: Martens
authors.forename: Joyce
authors.initials: J
authors.lastname: Doorn
authors.forename: Anouk
authors.initials: A
authors.lastname: Leusink
authors.forename: Cristina
authors.initials: C
authors.lastname: Olivo
authors.forename: Ruud
authors.initials: R
authors.lastname: Licht
authors.forename: Linda
authors.initials: L
authors.lastname: van Rijn
authors.forename: Claudia
authors.initials: C
authors.lastname: Gaspar
authors.forename: Riccardo
authors.initials: R
authors.lastname: Fodde
authors.forename: Frank
authors.initials: F
authors.lastname: Janssen
authors.forename: Clemens
authors.initials: C
authors.lastname: van Blitterswijk
authors.forename: Jan
authors.initials: J
authors.lastname: de Boer
mesh_terms: D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D017370:Interleukin-11 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008954:Models, Biological; D010012:Osteogenesis; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D015398:Signal Transduction; D023822:Tissue Engineering / Q000379:methods*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D016207:Cytokines; C064269:FOSB protein, human; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; D017370:Interleukin-11; D016760:Proto-Oncogene Proteins c-fos; D016212:Transforming Growth Factor beta; D007334:Insulin-Like Growth Factor I; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases