Direct or indirect stimulation of adenosine A 2A receptors enhances bone regeneration as well as bone morphogenetic protein‐2
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Promoting bone regeneration and repair of bone defects is a need that has not been well met to date. We have previously found that adenosine, acting via receptors (A2AR) promotes wound healing and inhibits inflammatory osteolysis and hypothesized that A2AR might be a novel target to promote bone regeneration. Therefore, we determined whether direct A2AR stimulation or increasing endogenous adenosine concentrations via purine transport blockade with dipyridamole regulates bone formation. We determined whether coverage of a 3 mm trephine defect in a mouse skull with a collagen scaffold soaked in saline, bone morphogenetic protein‐2 (BMP‐2; 200 ng), 1 μM CGS21680 (A2AR agonist, EC 50 = 160 nM), or 1 μM dipyridamole (EC 50 = 32 nM) promoted bone regeneration. Microcomputed tomography examination demonstrated that CGS21680 and dipyridamole markedly enhanced bone regeneration as well as BMP‐2 8 wk after surgery (60 ± 2%, 79 ± 2%, and 75 ± 1% bone regeneration, respectively, vs. 32 ± 2% in control, P < 0.001). Blockade by a selective A2AR antagonist (ZM241385, 1 μM) or deletion of A2AR abrogated the effect of CGS21680 and dipyridamole on bone regeneration. Both CGS21680 and dipyridamole treatment increased alkaline phosphatase‐positive osteoblasts and diminished tartrate resistance acid phosphatase‐positive osteoclasts in the defects. In vivo imaging with a fluorescent dye for new bone formation revealed a strong fluorescent signal in treated animals that was equivalent to BMP‐2. In conclusion, stimulation of A2AR by specific agonists or by increasing endogenous adenosine levels stimulates new bone formation as well as BMP‐2 and represents a novel approach to stimulating bone regeneration.—Mediero, A., Wilder, T., Perez‐Aso, M., Cronstein, B. N. Direct or indirect stimulation of adenosine A 2A receptors enhances bone regeneration as well as bone morphogenetic protein‐2. FASEB J. 29, 1577‐1590 (2015). www.fasebj.org
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A major mechanism of caffeine in organs is its direct and indirect effects on bone metabolism through competitive inhibition of four adenosine receptors (A1, A2A, A2B, A3), which are expressed in undifferentiated osteoblast precursors and differentiated osteoblasts.
“Evidence has shown that a major mechanism of caffeine in organs is its direct and indirect effects on bone metabolism through competitive inhibition of four adenosine receptors, including A1, A2A, A2B and A3 adenosine, which are expressed in undifferentiated osteoblast precursors and differentiated osteoblasts [41, 42].”
From Association between caffeine consumption and bone mineral density in children and adolescent: Observational and Mendelian randomization study (2023) · cites this paper as [42]
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- Authors
- Mediero, A., Wilder, T., Perez‐Aso, M., & Cronstein, B. N.
- Affiliations
- NYU Langone Health (US)
- Divisions of Translational Medicine and Rheumatology Department of Medicine New York University Langone Medical Center New York New York USA
- Corresponding author
- Cronstein, Bruce N.
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2015-01-08
- Volume
- 29
- Issue
- 4
- Pages
- 1577-1590
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- PMC
- PMC4396602
- OpenAlex
- W2124167914
- Cited by
- 103
- References
- 54
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 8 · 2023: 11 · 2022: 13 · 2021: 8 · 2020: 8 · 2019: 12 · 2018: 12 · 2017: 7 · 2016: 7 · 2015: 2
- FWCI
- 7.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The FASEB Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AR56672, AR54897, AR046121)
- Takeda Pharmaceuticals North America
- Celgene
- AstraZeneca
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Physical Sciences › Engineering › Biomedical Engineering › Bone Tissue Engineering Materials
- Keywords
- adenosine A2A receptor, bone regeneration, BMP-2, dipyridamole, CGS 21680, ZM241385, osteoblasts, osteoclasts, calvarial defect, endogenous adenosine, bone formation
- MeSH terms
- Adenosine, Animals, Bone Regeneration, Cell Count, Dipyridamole, Female, Mice, Inbred C57BL, Osteoblasts, Osteoclasts, Phenethylamines, Mice, Knockout, Receptor, Adenosine A2A, Mice, Bone Morphogenetic Protein 2, Adenosine A2 Receptor Agonists
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