Cited by 103Adenosine and Purinergic SignalingBone Metabolism and DiseasesBone Tissue Engineering Materials

Direct or indirect stimulation of adenosine A 2A receptors enhances bone regeneration as well as bone morphogenetic protein‐2

Open access
Mediero, Aránzazu, Wilder, Tuere, Perez‐Aso, Miguel, Cronstein, Bruce N.·2015·The FASEB Journal

Abstract

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

Integrity signals

Registry

Crossref · 10.1096/fj.14-265066

Cites

53 of 53 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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].”

Cites

Flagged first, then by citations

1 of the 54 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

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
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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review