title: Ticagrelor regulates osteoblast and osteoclast function and promotes bone formation in vivo via an adenosine-dependent mechanism.
abstract: As many as 10% of bone fractures heal poorly, and large bone defects resulting from trauma, tumor, or infection may not heal without surgical intervention. Activation of adenosine A2Areceptors (A2ARs) stimulates bone formation. Ticagrelor and dipyridamole inhibit platelet function by inhibiting P2Y12receptors and platelet phosphodiesterase, respectively, but share the capacity to inhibit cellular uptake of adenosine and thereby increase extracellular adenosine levels. Because dipyridamole promotes bone regeneration by an A2AR-mediated mechanism we determined whether ticagrelor could regulate the cells involved in bone homeostasis and regeneration in a murine model and whether inhibition of P2Y12or indirect A2AR activation via adenosine was involved. Ticagrelor, dipyridamole and the active metabolite of clopidogrel (CAM), an alternative P2Y12antagonist, inhibited osteoclast differentiation and promoted osteoblast differentiation in vitro. A2AR blockade abrogated the effects of ticagrelor and dipyridamole on osteoclast and osteoblast differentiation whereas A2BR blockade abrogated the effects of CAM. Ticagrelor and CAM, when applied to a 3-dimentional printed resorbable calcium-triphosphate/hydroxyapatite scaffold implanted in a calvarial bone defect, promoted significantly more bone regeneration than the scaffold alone and as much bone regeneration as BMP-2, a growth factor currently used to promote bone regeneration. These results suggest novel approaches to targeting adenosine receptors in the promotion of bone regeneration.-Mediero, A., Wilder, T., Reddy, V. S. R., Cheng, Q., Tovar, N., Coelho, P. G., Witek, L., Whatling, C., Cronstein, B. N. Ticagrelor regulates osteoblast and osteoclast function and promotes bone formation in vivo via an adenosine-dependent mechanism.
authors: Bone and Joint Research Unit, Instituto de Investigación Sanitaria, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain.
authors: Aránzazu
authors: A
authors: Mediero
authors: Division of Translational Medicine, Department of Medicine, New York University (NYU)-Langone Medical Center, New York, New York, USA.
authors: Tuere
authors: T
authors: Wilder
authors: Department of Biomaterials and Biomimetics, NYU College of Dentistry, New York, New York, USA; and.
authors: Vishnu S R
authors: VS
authors: Reddy
authors: Division of Translational Medicine, Department of Medicine, New York University (NYU)-Langone Medical Center, New York, New York, USA.
authors: Qian
authors: Q
authors: Cheng
authors: Department of Biomaterials and Biomimetics, NYU College of Dentistry, New York, New York, USA; and.
authors: Nick
authors: N
authors: Tovar
authors: Department of Biomaterials and Biomimetics, NYU College of Dentistry, New York, New York, USA; and.
authors: Paulo G
authors: PG
authors: Coelho
authors: Department of Biomaterials and Biomimetics, NYU College of Dentistry, New York, New York, USA; and.
authors: Lukasz
authors: L
authors: Witek
authors: AstraZeneca R&D Mölndal, Cardiovascular and Metabolic Diseases Innovative Medicine Unit, Translational Sciences, Mölndal, Sweden.
authors: Carl
authors: C
authors: Whatling
authors: Division of Translational Medicine, Department of Medicine, New York University (NYU)-Langone Medical Center, New York, New York, USA.
authors: Bruce N
authors: BN
authors: Cronstein
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001861:Bone Regeneration / Q000187:drug effects; D000077144:Clopidogrel; D004176:Dipyridamole / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D000077486:Ticagrelor; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D043705:Receptor, Adenosine A2A; D004176:Dipyridamole; D000077144:Clopidogrel; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine
keywords: 3-D HA/β-TCP scaffolds; A2AR; antiplatelet drugs; bone regeneration