Disabling of receptor activator of nuclear factor-κB (RANK) receptor complex by novel osteoprotegerin-like peptidomimetics restores bone loss in vivo
Disabling of receptor activator of nuclear factor-κB (RANK) receptor complex by novel osteoprotegerin-like peptidomimetics restores bone loss in vivo
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DOI：
10.1074/jbc.m309690200
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发表时间：
2004-02-27
影响因子：
4.8
通讯作者：
Murali, R
中科院分区：
文献类型：
--
作者：
Cheng, X;Kinosaki, M;Murali, R
肿瘤坏死因子家族配体、肿瘤坏死因子相关激活诱导细胞因子(TRANCE)及其受体、核因子-kappaB受体激活剂(RANK)和护骨素(OPG)是骨重建中破骨细胞发育和激活的调节因子。持续的破骨细胞激活会导致骨质疏松等骨质疏松，并导致溶骨性转移。在这里，我们报告了一种合理设计的模拟骨保护素的小分子化合物，在体外抑制破骨细胞的形成，并在骨质疏松的动物模型中限制骨丢失。其中，OP3-4在体外能显著抑制破骨细胞的形成(IC50=10微米)，并能有效地抑制去卵巢小鼠的骨丢失。与阻止RANK结合的可溶性OPG受体不同，OP3-4具有调节RANK信号通路的能力，并通过促进有缺陷的受体复合体来改变RANK受体复合体的生物学功能。这些特点表明，OPG衍生的小分子可以作为探针来了解RANK-TRANCE-OPG受体的复杂生物学功能，也可以作为开发更有用的炎症和骨病治疗剂的平台。
The tumor necrosis factor family ligand, tumor necrosis factor-related activation-induced cytokine ( TRANCE), and its receptors, receptor activator of nuclear factor-kappaB ( RANK) and osteoprotegerin (OPG), are known to be regulators of development and activation of osteoclasts in bone remodeling. Sustained osteoclast activation that occurs through TRANCE-RANK causes osteopenic disorders such as osteoporosis and contributes to osteolytic metastases. Here, we report a rationally designed small molecule mimic of osteoprotegerin to inhibit osteoclast formation in vitro and limit bone loss in an animal model of osteoporosis. One of the mimetics, OP3-4, significantly inhibited osteoclast formation in vitro (IC50 = 10 muM) and effectively inhibited total bone loss in ovariectomized mice at a dosage of 2 mg/kg/day. Unlike soluble OPG receptors, which preclude TRANCE binding to RANK, OP3-4 shows the ability to modulate RANK-TRANCE signaling pathways and alters the biological functions of the RANK-TRANCE receptor complex by facilitating a defective receptor complex. These features suggest that OPG-derived small molecules can be used as a probe to understand complex biological functions of RANK-TRANCE-OPG receptors and also can be used as a platform to develop more useful therapeutic agents for inflammation and bone disease.