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 A receptors (ARs) stimulates bone formation. Ticagrelor and dipyridamole inhibit platelet function by inhibiting P2Y receptors 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 AR-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 or indirect AR activation via adenosine was involved. Ticagrelor, dipyridamole and the active metabolite of clopidogrel (CAM), an alternative P2Y antagonist, inhibited osteoclast differentiation and promoted osteoblast differentiation in vitro. AR blockade abrogated the effects of ticagrelor and dipyridamole on osteoclast and osteoblast differentiation whereas AR 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.

Repair of Critical‐Sized Long Bone Defects Using Dipyridamole‐Augmented 3D‐Printed Bioactive Ceramic Scaffolds

“…DIPY is a well‐known anti‐thrombotic agent and recently it has been investigated for its osteogenic potential via adenosine receptor ligation. Activation of the adenosine A 2A receptor has demonstrated the ability to attenuate osteoclast differentiation and upregulate osteoblast differentiation . DIPY‐induced A 2A R ligation has been reported to augment critical bone defect healing to a similar degree as BMP‐2.…”

“…Data collected from studies both in vitro and in vivo have also demonstrated that osteoblast activity is positively modulated by A 2A R ligation; in vivo work has demonstrated adenosine‐stimulated osteogenesis regenerative potential in murine calvarial models . Calvarial defects replaced with 3D‐printed scaffolds coated with A 2A R agonists healed bone as effectively as rhBMP‐2, without the unpredictability and expense that have been previously associated with rhBMPs. More recently, our group has demonstrated that these principles have shown translational promise in large animal calvarial defects, with the adenosine A 2A R indirect agonist dipyridamole (DIPY) exerting a significant effect on bone regenerative capacity.…”

The role of 3D printing in treating craniomaxillofacial congenital anomalies

“…Many bioactive agents have been assessed as potential bone regenerative therapeutics. Among these molecules, those that activate purinergic receptors have recently been reported to have significant therapeutic potential without undesired side effects that often accompany other notable compounds such as recombinant human bone morphogenetic protein (rhBMP-2) (Bekisz et al, 2017;Costa et al, 2011;Mediero & Cronstein, 2013;Mediero, Wilder, Perez-Aso, & Cronstein, 2015;Mediero, Frenkel et al, 2012;Mediero et al, 2016).…”

Netrins & Semaphorins: Novel regulators of the immune response

“…These findings point to the possible therapeutic role of targeting Netrin-1 in overactive osteoclast diseases. As such, antibody-mediated blockade of Netrin-1 and Unc5b, but not DCC, reduced paw inflammation, bone erosion and osteoclast numbers in a mouse model of inflammatory arthritis [71]. …”