Adenosine A 1 receptors regulate bone resorption in mice: Adenosine A 1 receptor blockade or deletion increases bone density and prevents ovariectomy‐induced bone loss in adenosine A 1 receptor–knockout mice

Objective Accelerated osteoclastic bone resorption plays a central role in the pathogenesis of osteoporosis and other bone diseases. Because identifying the molecular pathways that regulate osteoclast activity provides a key to understanding the causes of these diseases and developing new treatments, we studied the effect of adenosine A 1 receptor blockade or deletion on bone density. Methods The bone mineral density (BMD) in adenosine A 1 receptor–knockout (A 1 R‐knockout) mice was analyzed by dual x‐ray absorptiometry (DXA) scanning, and the trabecular and cortical bone volume was determined by microfocal computed tomography (micro‐CT). The mice were ovariectomized or sham‐operated, and 5 weeks after surgery, when osteopenia had developed, several parameters were analyzed by DXA scanning and micro‐CT. A histologic examination of bones obtained from A 1 R‐knockout and wild‐type mice was carried out. Visualization of osteoblast function (bone formation) after tetracycline double‐labeling was performed by fluorescence microscopy. Results Micro‐CT analysis of bones from A 1 R‐knockout mice showed significantly increased bone volume. Electron microscopy of bones from A 1 R‐knockout mice showed the absence of ruffled borders of osteoclasts and osteoclast bone resorption. Immunohistologic analysis demonstrated that although osteoclasts were present in the A 1 R‐knockout mice, they were smaller and often not associated with bone. No morphologic changes in osteoblasts were observed, and bone‐labeling studies revealed no change in the bone formation rates in A 1 R‐knockout mice. Conclusion These results suggest that the adenosine A 1 receptor may be a useful target in treating diseases characterized by excessive bone turnover, such as osteoporosis and prosthetic joint loosening.