Adenosine A _2A 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 A2A receptors (A2AR) mediate potent anti-inflammatory effects in many tissues and prevent osteoclast differentiation. We tested the hypothesis that an A2AR agonist could reduce osteoclast-mediated bone resorption in a murine calvaria model of wear-particle–induced bone resorption. C57Bl/6 and A2A knockout (A2ARKO) mice received ultrahigh-molecular weight polyethylene particles (UHMWPE) and were treated daily with either saline or the A2AR 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 A2AKO mice, CGS21680 did not affect osteoclast-mediated bone resorption or inflammation. Levels of bone-resorption markers receptor activator of nuclear factor-kB (RANK), RANK ligand (RANKL), cathepsin K, CD163, and osteopontin were reduced following CGS21680 treatment, together with a reduction in osteoclasts. Secretion of interleukin 1β (IL-1β) and TNFα 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 A2AR agonist could enhance implant survival, delaying or eliminating the need for revision arthroplastic surgery.

Direct or indirect stimulation of adenosine A 2A receptors enhances bone regeneration as well as bone morphogenetic protein‐2

“…Here we describe, for the first time, a direct effect of A2AR activation on bone regeneration in vivo, either via direct activation of the receptor or by enhancing extracellular adenosine levels by blockade of Ent1 transporter. Previously, we reported that activation of the A2AR inhibits osteoclast differentiation (17)(18)(19) both in vitro and . Immunohistochemistry for markers of bone remodeling.…”

“…The adenosine A1R is critical for osteoclast differentiation and function; A1R blockade or deletion suppresses receptor activated by NF-kB ligand (RANKL)-induced NF-kB activation in vitro, increases bone density, and prevents ovariectomy-induced bone loss in vivo (14)(15)(16). Stimulation of the A2AR inhibits M-CSF/RANKL-stimulated osteoclast differentiation and function in vitro, in part by decreasing IL-1b and TNF-a secretion (17), and the selective A2AR agonist CGS21680 reduces wear particleinduced bone pitting and porosity in vivo, increasing cortical bone and bone volume compared with control mice (18). Strong evidence implicates a role for A2BR in osteoblast differentiation and function (19).…”

The role of purinergic signalling in the musculoskeletal system

“…However, more recent work has suggested that stimulation of the A2A receptor by adenosine or selective agonists can both stimulate (Pellegatti et al, 2011) and inhibit (Mediero et al, 2012b) osteoclast formation. A2A receptor activation has also been shown to prevent the osteolysis that occurs during prosthesis loosening, a common cause of joint implant failure (Mediero et al, 2012a). Pellegatti et al (2011) reported that the A1 receptor was only weakly expressed by osteoclasts and activation of the A1 receptor was recently shown to have no effect on mouse osteoclasts (Pellegatti et al, 2011;He et al, 2012).…”

Regulation of bone and cartilage by adenosine signaling

“…In terms of the therapeutic role of A2AR receptors, in patients with inflammatory bone disease, A2AR agonists reduce bone pitting and loss by decreasing the number of osteoclasts and the degree of inflammation [61]. A more recent study demonstrated that weekly low-dose methotrexate (MTX) injections decreased bone pitting but treatment with ZM241385, an A2AR antagonist, or knockout of A2AR abrogated this effect.…”