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.


CONCLUSIONS
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.
Kara
Firas M
FM
New York University School of Medicine, New York, NY, USA.
Doty
Stephen B
SB
Boskey
Adele
A
Goldring
Steven
S
Zaidi
Mone
M
Fredholm
Bertil B
BB
Cronstein
Bruce N
BN
D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D015519:Bone Density / Q000502:physiology; D001862:Bone Resorption / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D010010:Osteoclasts / Q000502:physiology / Q000648:ultrastructure; D010052:Ovariectomy; D010641:Phenotype; D043682:Receptor, Adenosine A1 / Q000235:genetics* / Q000378:metabolism*; D055114:X-Ray Microtomography
D058916:Adenosine A1 Receptor Antagonists; D043682:Receptor, Adenosine A1