Premium
Ticagrelor regulates osteoblast and osteoclast function and promotes bone formation in vivo via an adenosine‐dependent mechanism
Author(s) -
Mediero Aránzazu,
Wilder Tuere,
Reddy Vishnu S. R.,
Cheng Qian,
Tovar Nick,
Coelho Paulo G.,
Witek Lukasz,
Whatling Carl,
Cronstein Bruce N.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201600616r
Subject(s) - osteoclast , ticagrelor , p2y12 , adenosine , osteoblast , chemistry , purinergic signalling , microbiology and biotechnology , adenosine receptor , bone remodeling , purinergic receptor , pharmacology , bone resorption , medicine , platelet , receptor , biology , clopidogrel , biochemistry , in vitro , agonist , platelet aggregation , aspirin
As many as 10% of bone fractures heal poorly, and large bone defects resulting fromtrauma, tumor, or infection may not heal without surgical intervention. Activation of adenosine A 2A receptors (A 2A Rs) stimulates bone formation. Ticagrelor and dipyridamole inhibit platelet function by inhibiting P2Y 12 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 A 2A R‐mediated mechanism we determined whether ticagrelor could regulate the cells involved in bone homeostasis and regeneration in a murine model and whether inhibition of P2Y 12 or indirect A 2A R activation via adenosine was involved. Ticagrelor, dipyridamole and the active metabolite of clopidogrel (CAM), an alternative P2Y 12 antagonist, inhibited osteoclast differentiation and promoted osteoblast differentiation in vitro . A 2A R blockade abrogated the effects of ticagrelor and dipyridamole on osteoclast and osteoblast differentiation where as A 2B R 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. FASEB J. 30, 3887–3900 (2016) www.fasebj.org