Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling.
Adenosine is an endogenous nucleoside that modulates many physiological processes through four receptor subtypes (A(1), A(2a), A(2b), A(3)). Previous work from our laboratory has uncovered a critical role for adenosine A(1) receptor (A(1) R) in osteoclastogenesis both in vivo and in vitro. Our current work focuses on understanding the details of how A(1) R modulates the receptor activator of NF-κB ligand (RANKL)-induced signaling in osteoclastogenesis. Osteoclasts were generated from mouse bone marrow precursors in the presence of RANKL and macrophage-colony stimulating factor. A pharmacological antagonist of A(1) R (DPCPX) inhibited RANKL-induced osteoclast differentiation, including osteoclast-specific genes (Acp5, MMP9, β(3) Integrin, α(v) Integrin, and CTSK) and osteoclast-specific transcription factors such as c-fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) expression in a dose-dependent manner. DPCPX also inhibited RANKL-induced activation of NF-κB and JNK/c-Jun but had little effect on other mitogen-activated protein kinases (p38 and Erk). Finally, immunoprecipitation analysis showed that blockade of A(1)R resulted in disruption of the association of tumor necrosis factor receptor-associated factor 6 (TRAF6) and transforming growth factor-β-activated kinase 1 (TAK1), a signaling event that is important for activation of NF-κB and JNK, suggesting the participation of adenosine/A(1)R in early signaling of RANKL. Collectively, these data demonstrated an important role of adenosine, through A(1)R in RANKL-induced osteoclastogenesis.
New York University School of Medicine, New York, NY 10016, USA.
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D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology; D053245:RANK Ligand / Q000502:physiology; D043682:Receptor, Adenosine A1 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism* / Q000502:physiology; D000099151:MAP Kinase Kinase Kinase 7
D058916:Adenosine A1 Receptor Antagonists; D020930:MAP Kinase Kinase Kinases; D053245:RANK Ligand; D043682:Receptor, Adenosine A1; D048029:TNF Receptor-Associated Factor 6; D000099151:MAP Kinase Kinase Kinase 7; C505689:Tnfsf11 protein, mouse