| Abstrakt: |
Adenosine is generated in increased concentrations at sites of injury/hypoxia and mediates a variety of physiological and pharmacological effects via G protein–coupled receptors (A1, A2A, A2B, and A3). Because all adenosine receptors are expressed on osteoclasts, we determined the role of A2Areceptor in the regulation of osteoclast differentiation. Differentiation and bone resorption were studied as the macrophage colony-stimulating factor-1–receptor activator of NF-κB ligand formation of multinucleated tartrate-resistant acid phosphatase (TRAP)–positive cells from primary murine bone marrow–derived precursors. A2Areceptor and osteoclast marker expression levels were studied by RT-PCR. Cytokine secretion was assayed by enzyme-linked immunosorbent assay. In vivoexamination of A2Aknockout (KO)/control bones was determined by TRAP staining, micro–computed tomography, and electron microscopy. The A2Areceptor agonist, CGS21680, inhibited osteoclast differentiation and function (half maximal inhibitory concentration, 50 nmol/L), increased the percentage of immature osteoclast precursors, and decreased IL-1β and tumor necrosis factor-α secretion, an effect that was reversed by the A2Aantagonist, ZM241385. Cathepsin K and osteopontin mRNA expression increased in control and ZM241385-pretreated osteoclasts, and this was blocked by CGS21680. Micro–computed tomography of A2AKO mouse femurs showed a significantly decreased bone volume/trabecular bone volume ratio, decreased trabecular number, and increased trabecular space. A2AKO femurs showed an increased TRAP-positive osteoclast. Electron microscopy in A2AKO femurs showed marked osteoclast membrane folding and increased bone resorption. Thus, adenosine, acting via the A2Areceptor, inhibits macrophage colony-stimulating factor-1–receptor activator of NF-κB ligand–stimulated osteoclast differentiation and may regulate bone turnover under conditions in which adenosine levels are elevated. |
