Adenosine A2A Receptor Activation Prevents Wear Particle-Induced Osteolysis

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 kappa B (RANK), RANK ligand, cathepsin K, CD163, and osteopontin were reduced after CGS21680 treatment, together with a reduction in osteoclasts. Secretion of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha 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.