title: 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.
abstract: 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.
authors.affiliation: New York University School of Medicine, New York, NY, USA.
authors.forename: Firas M
authors.initials: FM
authors.lastname: Kara
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Doty
authors.forename: Adele
authors.initials: A
authors.lastname: Boskey
authors.forename: Steven
authors.initials: S
authors.lastname: Goldring
authors.forename: Mone
authors.initials: M
authors.lastname: Zaidi
authors.forename: Bertil B
authors.initials: BB
authors.lastname: Fredholm
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Cronstein
mesh_terms: 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
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D043682:Receptor, Adenosine A1