Journal
PURINERGIC SIGNALLING
Volume 8, Issue 2, Pages 327-337Publisher
SPRINGER
DOI: 10.1007/s11302-012-9292-9
Keywords
Adenosine A(1) receptor; Osteoclastogenesis; TAK1; TRAF6; NF-kappa B
Categories
Funding
- National Institutes of Health [AR56672, AR56672S1, AR54897]
- NYU-HHC Clinical and Translational Science Institute [UL1RR029893]
- Vilcek Foundation
- King Pharmaceuticals
- NIH
- OSI Pharmaceuticals
- URL Pharmaceuticals, Inc.
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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-kappa B 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, beta(3) Integrin, alpha(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-kappa B 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-beta-activated kinase 1 (TAK1), a signaling event that is important for activation of NF-kappa B 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.
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