Research ArticleBONE REPAIR

Adenosine A2A Receptor Activation Prevents Wear Particle–Induced Osteolysis

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Science Translational Medicine  23 May 2012:
Vol. 4, Issue 135, pp. 135ra65
DOI: 10.1126/scitranslmed.3003393

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Agonist Abates Bone Destruction

Surgeons perform tens of thousands of total hip replacements per year in the United States. Despite the prevalence of hip implants, they often loosen over time, making the patient return to the surgeon for a revision procedure, typically involving implant removal. Prosthesis loosening has been associated with a breakdown of the implant materials into tiny wear particles, which leads to inflammation in the joint and destruction of the bone (“pitting”) via the small signaling molecule adenosine. Mediero and colleagues have now found that by stimulating the adenosine A2A receptor (A2AR), they can prevent wear particle–induced bone damage and inflammation at the implant site.

To simulate wear particle exposure, the authors injected mice with ultrahigh–molecular weight polyethylene (UHMWPE) particles. After 2 weeks, these mouse calvaria showed pitting and increased porosity compared to particle-free mice. Giving the mice CGS21680, an adenosine A2AR agonist, at the same time as the wear particles reduced bone destruction and inflammation. Mechanism was confirmed in A2AR knockout mice, where the agonist had no effect on bone pitting. CGS21680 also inhibited differentiation of human-derived osteoclast precursor cells (from the bone marrow of four patients) into osteoclasts—the cell type that chews up bone. This suggests that the agonist will have a similar effect on human cells and could be used to prevent wear particle–induced damage in people, although only future clinical trials will confirm this. The authors indicate that this agonist could be included in bone cement or as a coating on prostheses to exert its bone-protective effects over time and thus prevent painful revision procedures.

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