Adenosine receptor subtype expression and activation influence the differentiation of mesenchymal stem cells to osteoblasts and adipocytes

Osteoblasts and adipocytes differentiate from a common precursor cell, the mesenchymal stem cell (MSC). Adenosine is known to signal via four adenosine receptor subtypes, and significantly, recent findings indicate that these may play a role in MSC differentiation. We therefore investigated adenosin...

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Bibliographic Details
Published in:Journal of bone and mineral research 2011-09, Vol.26 (9), p.2112-2124
Main Authors: Gharibi, Borzo, Abraham, Anju A, Ham, Jack, Evans, Bronwen AJ
Format: Article
Language:English
Subjects:
ADENOSINE RECEPTOR
Adenosine-5'-(N-ethylcarboxamide) - pharmacology
ADIPOCYTE
Adipocytes - cytology
Adipocytes - drug effects
Adipocytes - metabolism
Adipogenesis - drug effects
Adipogenesis - genetics
Alkaline Phosphatase - metabolism
Animals
Biological and medical sciences
Biomarkers - metabolism
Blotting, Western
Calcification, Physiologic - drug effects
Calcification, Physiologic - genetics
Cell Count
Cell Differentiation - genetics
Cyclic AMP - metabolism
DIFFERENTIATION
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation - drug effects
Humans
Lipid Metabolism - drug effects
MESENCHYMAL STEM CELL
Mesenchymal Stromal Cells - cytology
Mesenchymal Stromal Cells - drug effects
Mesenchymal Stromal Cells - metabolism
OSTEOBLAST
Osteoblasts - cytology
Osteoblasts - drug effects
Osteoblasts - enzymology
Osteogenesis - drug effects
Osteogenesis - genetics
Purinergic P1 Receptor Agonists - pharmacology
Purinergic P1 Receptor Antagonists - pharmacology
Rats
Receptors, Purinergic P1 - genetics
Receptors, Purinergic P1 - metabolism
Signal Transduction - drug effects
Skeleton and joints
Vertebrates: osteoarticular system, musculoskeletal system
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Summary:Osteoblasts and adipocytes differentiate from a common precursor cell, the mesenchymal stem cell (MSC). Adenosine is known to signal via four adenosine receptor subtypes, and significantly, recent findings indicate that these may play a role in MSC differentiation. We therefore investigated adenosine receptor expression and activation during the differentiation of MSCs to osteoblasts and adipocytes. The A2BR was dominant in MSCs, and its expression and activity were transiently upregulated at early stages of osteoblastic differentiation. Both activation and overexpression of A2BR induced the expression of osteoblast‐related genes [Runx2 and alkaline phosphatase (ALP)], as well as ALP activity, and stimulation increased osteoblast mineralization. The expression of A2AR was upregulated during later stages of osteoblastic differentiation, when its activation stimulated ALP activity. Differentiation of MSCs to adipocytes was accompanied by significant increases in A1R and A2AR expression, and their activation was associated with increased adipogenesis. Enhanced A2AR expression was sufficient to promote expression of adipocyte‐related genes (PPARγ and C/EBPα), and its activation resulted in increased adipocytic differentiation and lipid accumulation. In contrast, the A1R was involved mainly in lipogenic activity of adipocytes rather than in their differentiation. These results show that adenosine receptors are differentially expressed and involved in lineage‐specific differentiation of MSCs. We conclude, therefore, that fruitful strategies for treating diseases associated with an imbalance in the differentiation and function of these lineages should include targeting adenosine receptor signal pathways. Specifically, these research avenues will be useful in preventing or treating conditions with insufficient bone or excessive adipocyte formation. © 2011 American Society for Bone and Mineral Research
ISSN:0884-0431
1523-4681
DOI:10.1002/jbmr.424