cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo

Ramakrishnaiah Siddappa, Anton Martens, Joyce Doorn, Anouk Leusink, Cristina Olivo, Ruud Licht, Linda van Rijn, Claudia Gaspar, Riccardo Fodde, Frank Janssen, Clemens van Blitterswijk, Jan de Boer

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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.
Original languageEnglish
Pages (from-to)7281-7286
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number20
DOIs
Publication statusPublished - 2008

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Mesenchymal Stromal Cells
Osteogenesis
Bone and Bones
Interleukin-11
Tissue Engineering
Stromal Cells
Cyclic AMP-Dependent Protein Kinases
Insulin-Like Growth Factor I
Orthopedics
Clinical Trials
Pharmacology
Cytokines
In Vitro Techniques
Genes

Keywords

  • METIS-253659
  • IR-60305

Cite this

Siddappa, Ramakrishnaiah ; Martens, Anton ; Doorn, Joyce ; Leusink, Anouk ; Olivo, Cristina ; Licht, Ruud ; van Rijn, Linda ; Gaspar, Claudia ; Fodde, Riccardo ; Janssen, Frank ; van Blitterswijk, Clemens ; de Boer, Jan. / cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 20. pp. 7281-7286.
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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.",
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author = "Ramakrishnaiah Siddappa and Anton Martens and Joyce Doorn and Anouk Leusink and Cristina Olivo and Ruud Licht and {van Rijn}, Linda and Claudia Gaspar and Riccardo Fodde and Frank Janssen and {van Blitterswijk}, Clemens and {de Boer}, Jan",
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Siddappa, R, Martens, A, Doorn, J, Leusink, A, Olivo, C, Licht, R, van Rijn, L, Gaspar, C, Fodde, R, Janssen, F, van Blitterswijk, C & de Boer, J 2008, 'cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo' Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 20, pp. 7281-7286. https://doi.org/10.1073/pnas.0711190105

cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo. / Siddappa, Ramakrishnaiah; Martens, Anton; Doorn, Joyce; Leusink, Anouk; Olivo, Cristina; Licht, Ruud; van Rijn, Linda; Gaspar, Claudia; Fodde, Riccardo; Janssen, Frank; van Blitterswijk, Clemens; de Boer, Jan.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 20, 2008, p. 7281-7286.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo

AU - Siddappa, Ramakrishnaiah

AU - Martens, Anton

AU - Doorn, Joyce

AU - Leusink, Anouk

AU - Olivo, Cristina

AU - Licht, Ruud

AU - van Rijn, Linda

AU - Gaspar, Claudia

AU - Fodde, Riccardo

AU - Janssen, Frank

AU - van Blitterswijk, Clemens

AU - de Boer, Jan

PY - 2008

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N2 - 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.

AB - 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.

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JO - Proceedings of the National Academy of Sciences of the United States of America

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