Ticagrelor regulates osteoblast and osteoclast function and promotes bone formation in vivo via an adenosine-dependent mechanism

Aŕanzazu Mediero, Tuere Wilder, Vishnu S R Reddy, Qian Cheng, Nick Tovar, Paulo Coelho, Lukasz Witek, Carl Whatling, Bruce N. Cronstein

Research output: Contribution to journalArticle

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 A2A receptors (A2ARs) stimulates bone formation. Ticagrelor and dipyridamole inhibit platelet function by inhibiting P2Y12 receptors and platelet phosphodiesterase, respectively, but share the capacity to inhibit cellularuptake of adenosine and thereby increase extracellular adenosine levels. Because dipyridamole promotes bone regeneration by an A2AR-mediated mechanismwedeterminedwhether ticagrelor could regulate the cells involved inbonehomeostasis and regeneration in a murinemodel andwhether inhibition of P2Y12 or indirectA2ARactivation via adenosine was involved. Ticagrelor, dipyridamole and the active metabolite of clopidogrel (CAM), an alternative P2Y12 antagonist, 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 calvarialbonedefect,promotedsignificantlymoreboneregeneration 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.

Original languageEnglish (US)
Pages (from-to)3887-3900
Number of pages14
JournalFASEB Journal
Volume30
Issue number11
DOIs
StatePublished - Nov 1 2016

Fingerprint

Osteoblasts
Osteoclasts
Osteogenesis
Bone Regeneration
Adenosine
Dipyridamole
Bone
clopidogrel
Computer aided manufacturing
Blood Platelets
Platelets
Adenosine A2A Receptors
Scaffolds
Purinergic P1 Receptors
Bone Fractures
Phosphoric Diester Hydrolases
Durapatite
Regeneration
Intercellular Signaling Peptides and Proteins
Metabolites

Keywords

  • 3-D HA/b-TCP Scaffolds
  • Ar
  • Antiplatelet Drugs
  • Bone Regeneration

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Ticagrelor regulates osteoblast and osteoclast function and promotes bone formation in vivo via an adenosine-dependent mechanism. / Mediero, Aŕanzazu; Wilder, Tuere; Reddy, Vishnu S R; Cheng, Qian; Tovar, Nick; Coelho, Paulo; Witek, Lukasz; Whatling, Carl; Cronstein, Bruce N.

In: FASEB Journal, Vol. 30, No. 11, 01.11.2016, p. 3887-3900.

Research output: Contribution to journalArticle

Mediero, Aŕanzazu ; Wilder, Tuere ; Reddy, Vishnu S R ; Cheng, Qian ; Tovar, Nick ; Coelho, Paulo ; Witek, Lukasz ; Whatling, Carl ; Cronstein, Bruce N. / Ticagrelor regulates osteoblast and osteoclast function and promotes bone formation in vivo via an adenosine-dependent mechanism. In: FASEB Journal. 2016 ; Vol. 30, No. 11. pp. 3887-3900.
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