These antiinflammatory effects can be stymied, however. Caffeine and theophylline are adenosine-receptor blocking agents, Dr. Cronstein cautioned. They can “completely reverse” the antiinflammatory effects of methotrexate.
Inflammatory Osteolysis in Prosthesis Loosening
Adenosine-related mechanisms and axonal guidance proteins (i.e., Sema4D, netrin-1) may also be important in treating osteolysis in prosthesis loosening. Approximately 800,000 prosthetic joints are implanted annually in the U.S., Dr. Cronstein said. Despite changes in prostheses and surgical techniques, there has been no reduction in the rates of surgical revision—as many as 25% of patients undergo removal and replacements of the prosthesis. Inflammation caused by wear particles and osteoclast-mediated bone erosion are major contributors to prosthesis failure.
Laboratory studies show that adenosine receptors suppress Sema4D expression by osteoclasts. This is important, Dr. Cronstein noted, because Sema4D is highly expressed in periprosthetic soft tissue in patients who require prosthesis revision. Netrin-1 is similarly overexpressed in this case.
Stimulation of adenosine A2A receptors diminishes netrin-1 expression during wear particle–induced bone resorption. Stimulation of A2A can also suppress inflammatory bone disease by inhibiting osteoclast formation and function, stimulating interleukin (IL) 10 and osteoprotegerin expression, diminishing RANKL expression and diminishing wear particle–induced osteolysis.
Methotrexate-induced adenosine specifically diminishes arthritis-associated bone disease, and because of this mechanism, it may also be a potential therapy for mediating the inflammatory osteolysis in prosthesis loosening. According to Dr. Cronstein, the positive effects of methotrexate due to its A2A receptor–mediated mechanism are that it diminishes wear particle–induced osteolysis and wear particle–induced suppression of bone formation.
Dr. Cronstein discussed recently published research that he and his colleagues conducted, showing additional potential for A2A in mitigating osteolysis.2 The researchers concluded, “These results in mice suggest that site-specific delivery of an adenosine [A2A receptor] agonist could enhance implant survival, delaying or eliminating the need for revision arthroplastic surgery.”
In their animal study, the researchers noted that applying an adenosine A2A agonist inhibits wear particle–induced bone loss, diminishes wear particle–induced inflammation, reduces the number of osteoclasts in treated bone and restores bone formation.
Kimberly J. Retzlaff is a medical journalist based in Denver.