title: Adenosine A2A receptor activation prevents wear particle-induced osteolysis.
abstract: Prosthesis loosening, associated with wear particle-induced inflammation and osteoclast-mediated bone destruction, is a common cause for joint implant failure, leading to revision surgery. Adenosine A(2A) receptors (A(2A)Rs) mediate potent anti-inflammatory effects in many tissues and prevent osteoclast differentiation. We tested the hypothesis that an A(2A)R agonist could reduce osteoclast-mediated bone resorption in a murine calvaria model of wear particle-induced bone resorption. C57BL/6 and A(2A)R knockout (A(2A)R KO) mice received ultrahigh-molecular weight polyethylene particles and were treated daily with either saline or the A(2A)R agonist CGS21680. After 2 weeks, micro-computed tomography of calvaria demonstrated that CGS21680 reduced particle-induced bone pitting and porosity in a dose-dependent manner, increasing cortical bone and bone volume compared to control mice. Histological examination demonstrated diminished inflammation after treatment with CGS21680. In A(2A)R KO mice, CGS21680 did not affect osteoclast-mediated bone resorption or inflammation. Levels of bone resorption markers receptor activator of nuclear factor κB (RANK), RANK ligand, cathepsin K, CD163, and osteopontin were reduced after CGS21680 treatment, together with a reduction in osteoclasts. Secretion of interleukin-1β (IL-1β) and tumor necrosis factor-α was significantly decreased, whereas IL-10 was markedly increased in bone by CGS21680. These results in mice suggest that site-specific delivery of an adenosine A(2A)R agonist could enhance implant survival, delaying or eliminating the need for revision arthroplastic surgery.
authors.affiliation: Division of Translational Medicine, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Aránzazu
authors.initials: A
authors.lastname: Mediero
authors.forename: Sally R
authors.initials: SR
authors.lastname: Frenkel
authors.forename: Tuere
authors.initials: T
authors.lastname: Wilder
authors.forename: Wenjie
authors.initials: W
authors.lastname: He
authors.forename: Amitabha
authors.initials: A
authors.lastname: Mazumder
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Cronstein
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058908:Adenosine A2 Receptor Agonists / Q000627:therapeutic use*; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010014:Osteolysis / Q000517:prevention & control*; D010627:Phenethylamines / Q000627:therapeutic use*; D011475:Prosthesis Failure / Q000009:adverse effects*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*
chemical_list: D058908:Adenosine A2 Receptor Agonists; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine