cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo.
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.
Siddappa
Ramakrishnaiah
R
Department of Tissue Regeneration, Institute for Biomedical Technology, University of Twente, 7500 AE, Enschede, The Netherlands.
Martens
Anton
A
Doorn
Joyce
J
Leusink
Anouk
A
Olivo
Cristina
C
Licht
Ruud
R
van Rijn
Linda
L
Gaspar
Claudia
C
Fodde
Riccardo
R
Janssen
Frank
F
van Blitterswijk
Clemens
C
de Boer
Jan
J
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
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