title: Adenosine regulates bone metabolism via A1, A2A, and A2B receptors in bone marrow cells from normal humans and patients with multiple myeloma.
abstract: Multiple myeloma (MM) is characterized by osteolytic bone lesions with uncoupled bone remodeling. In this study, we examined the effects of adenosine and its receptors (A1R, A2AR, A2BR, and A3R) on osteoblast and osteoclast differentiation of cells derived from patients with MM and healthy control subjects. Mesenchymal stem cells and bone marrow-derived mononuclear cells were isolated from bone marrow and differentiated into osteoblasts and osteoclasts, respectively. A1R antagonist rolofylline and A2BR agonist BAY60-6583 inhibit osteoclast differentiation of cells from patients with MM in a dose-dependent manner, as shown by TRAP staining (IC50: 10 and ∼10 nM, respectively). BAY60-6583 and dipyridamole, a nucleoside transport inhibitor, stimulate osteoblast differentiation of cells from patients with MM, as measured by ALP activity at d 14 and Alizarin Red staining at d 21 (by 1.57±0.03- and 1.71±0.45-fold, respectively), which can be blocked by A2BR antagonist MRS1754. Consistently, real-time PCR showed a significant increase of mRNA of osteocalcin and osterix at d 14. The effect of adenosine and its receptors is consistent in patients with MM and healthy subjects, suggesting an intrinsic mechanism that is important in both MM bone metabolism and normal physiology. Furthermore, the effect of dipyridamole on osteoblast differentiation is diminished in both A2BR- and CD39-knockout mice. These results indicate that adenosine receptors may be useful targets for the treatment of MM-induced bone disease.
authors.affiliation: New York University School of Medicine, 550 First Ave., New York, NY 10016, USA.
authors.forename: Wenjie
authors.initials: W
authors.lastname: He
authors.forename: Amitabha
authors.initials: A
authors.lastname: Mazumder
authors.forename: Tuere
authors.initials: T
authors.lastname: Wilder
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Cronstein
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000241:Adenosine / Q000378:metabolism*; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004176:Dipyridamole / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009101:Multiple Myeloma / Q000378:metabolism*; D015675:Osteocalcin / Q000235:genetics; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D058906:Purinergic P1 Receptor Agonists / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014970:Xanthines / Q000494:pharmacology
chemical_list: D000081:Acetamides; D000631:Aminopyridines; C518875:BAY 60-6583; C423842:N-(4-cyanophenyl)-2-(4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy)acetamide; D058906:Purinergic P1 Receptor Agonists; D011687:Purines; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D014970:Xanthines; D015675:Osteocalcin; D004176:Dipyridamole; C073525:rolofylline; D000241:Adenosine
keywords: osteoblast differentiation; osteoclast differentiation; osteolytic bone disease