Adenosine A1 receptors (A1Rs) play a critical role in osteoclast formation and function
Adenosine A1 receptors (A1Rs) play a critical role in osteoclast formation and function
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DOI：
10.1096/fj.09-147447
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发表时间：
2010-07-01
期刊：
影响因子：
4.8
通讯作者：
Cronstein, Bruce N.
中科院分区：
文献类型：
--
作者：
Kara, Firas M.;Chitu, Violeta;Cronstein, Bruce N.
腺苷通过与一种或多种 G 蛋白偶联受体（A(1)R、A(2A)R、A(2B)R 和 A(3)R）相互作用调节多种生理过程。由于 A(1)R 占据促进人单核细胞在体外融合形成巨细胞，因此我们确定 A(1)R 占据是否同样促进破骨细胞功能和形成。从 C57Bl/6 雌性小鼠或 A(1)R 敲除小鼠及其野生型 (WT) 同窝小鼠中收获骨髓细胞 (BMC)，并在存在或不存在 A(1)R 拮抗剂的情况下，在集落刺激因子 1 和 NF-κ B 配体受体激活剂存在下分化为破骨细胞 1,3-二丙基-8-环戊基黄嘌呤（DPCPX）。对抗酒石酸酸性磷酸酶或 F-肌动蛋白染色样品中的破骨细胞形态进行分析，并通过牙本质的甲苯胺蓝染色评估骨吸收。 A(1)R 敲除小鼠的 BMC 形成的破骨细胞比 WT 小鼠的 BMC 少，并且 A(1)R 拮抗剂 DPCPX 抑制破骨细胞形成 (IC50 = 1 nM)，从而改变形态并降低骨吸收能力。 A(1)R 阻断增加了诱导分化为破骨细胞的 RAW264.7 细胞中 TRAF6 的泛素化和降解。这些研究表明腺苷通过与腺苷 A(1)R 相互作用在骨稳态中发挥关键作用，并进一步表明 A(1)R 可能是预防与炎症性疾病和更年期相关的骨质流失的新药理靶点。-Kara, F. M., Chitu, V., Sloane, J., Axelrod, M., Fredholm, B. B., Stanley, R., Cronstein, B. N. 腺苷 A(1) 受体 (A(1)Rs) 在破骨细胞的形成和功能中发挥着关键作用。 FASEB J. 24, 2325-2333 (2010)。 www.fasebj.org
Adenosine regulates a wide variety of physiological processes via interaction with one or more G-protein-coupled receptors (A(1)R, A(2A)R, A(2B)R, and A(3)R). Because A(1)R occupancy promotes fusion of human monocytes to form giant cells in vitro, we determined whether A(1)R occupancy similarly promotes osteoclast function and formation. Bone marrow cells (BMCs) were harvested from C57Bl/6 female mice or A(1)R-knockout mice and their wild-type (WT) littermates and differentiated into osteoclasts in the presence of colony stimulating factor-1 and receptor activator of NF-kappa B ligand in the presence or absence of the A(1)R antagonist 1,3-dipropyl-8-cyclopentyl xanthine (DPCPX). Osteoclast morphology was analyzed in tartrate-resistant acid phosphatase or F-actin-stained samples, and bone resorption was evaluated by toluidine blue staining of dentin. BMCs from A(1)R-knockout mice form fewer osteoclasts than BMCs from WT mice, and the A(1)R antagonist DPCPX inhibits osteoclast formation (IC50 = 1 nM), with altered morphology and reduced ability to resorb bone. A(1)R blockade increased ubiquitination and degradation of TRAF6 in RAW264.7 cells induced to differentiate into osteoclasts. These studies suggest a critical role for adenosine in bone homeostasis via interaction with adenosine A(1)R and further suggest that A(1)R may be a novel pharmacologic target to prevent the bone loss associated with inflammatory diseases and menopause.-Kara, F. M., Chitu, V., Sloane, J., Axelrod, M., Fredholm, B. B., Stanley, R., Cronstein, B. N. Adenosine A(1) receptors (A(1)Rs) play a critical role in osteoclast formation and function. FASEB J. 24, 2325-2333 (2010). www.fasebj.org