RANK Ligand is a Bone Anabolic Agent

RANK Ligand 是一种骨合成代谢剂

• 批准号: 7118802
• 负责人: Steven L Teitelbaum
• 金额: $ 33.43万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7118802
• 关键词: DNA binding protein; DNA footprinting; SDS polyacrylamide gel electrophoresis; autoradiography; biological signal transduction; bone development; collagenase; disease /disorder prevention /control; gel mobility shift assay; high performance liquid chromatography; immunoprecipitation; laboratory mouse; mass spectrometry; mitogen activated protein kinase; nuclear factor kappa beta; osteoblasts; osteogenesis; osteoporosis; osteoprotegerin; polymerase chain reaction; site directed mutagenesis; western blottings

DESCRIPTION (provided by applicant): Treatment of osteopenic disorders has relied, to-date, on anti-resorptive drugs such as estrogens and bisphosphonates. While these agents often retard progressive bone loss, they are not effective in reversing the established osteoporotic lesion, nor are they typically capable of curing patients already afflicted with the disease. The dramatic effect of parathyroid hormone as a potential clinical bone anabolic drug underscores the hypothesis that substantial enhancement of skeletal mass requires stimulation of bone formation. Thus, identification of molecules, which promote systemic osteogenesis, is a major focus of anti-osteoporosis research. We have made the surprising observation that the key osteoclastogenic cytokine, RANK ligand (RANKL), when administered subcutaneously as a GST-fusion protein, is a potent bone anabolic agent. This compound dramatically enhances osteoblastogenesis and, within one week, stimulates exuberant bone formation, as detected radiographically, histologically and densitometrically. Importantly, GST-RANKL, at doses inducing as much as a 25-fold increase in osteoblast (OB) number, does not promote osteoclastogenesis in vivo. We also have established that OBs, and their precursors, are direct targets of GST-RANKL and have shown that collagen type I synthesis, by these cells, is greatly accelerated when they are exposed to the fusion protein. These data position GST-RANKL, or its derivatives, as potential bone anabolic, anti-osteoporosis agents. We therefore hypothesize that (1) GST-RANKL enhances OBs function by distinct signal pathways; (2) GST-RANKL, transcriptionally and/or post-transcriptionally, induces collagen type I synthesis by OBs; and (3) GST-RANKL prevents and/or reverses osteoporosis. Our Specific Aims are therefore to: (1) identify the signal pathways by which GST-RANKL enhances OB function; (2) identify the mechanism by which GST-RANKL induces collagen type I synthesis by OBs; and (3) determine if GST-RANKL prevents and/or reverses osteoporosis.

描述（由申请人提供）：迄今为止，骨质减少疾病的治疗依赖于抗骨吸收药物，例如雌激素和双膦酸盐。虽然这些药物通常可以延缓进行性骨质流失，但它们不能有效逆转已形成的骨质疏松病变，通常也不能治愈已经患有该疾病的患者。甲状旁腺激素作为一种潜在的临床骨合成代谢药物的巨大作用强调了这样的假设：骨骼质量的显着增强需要刺激骨形成。因此，促进全身成骨的分子的鉴定是抗骨质疏松症研究的主要焦点。我们惊奇地发现，关键的破骨细胞因子 RANK 配体 (RANKL)，当作为 GST 融合蛋白皮下施用时，是一种有效的骨合成代谢剂。这种化合物可显着增强成骨细胞生成，并在一周内刺激旺盛的骨形成，如放射照相、组织学和密度测定所检测到的。重要的是，GST-RANKL 在诱导成骨细胞 (OB) 数量增加 25 倍的剂量下，不会促进体内破骨细胞生成。我们还确定 OB 及其前体是 GST-RANKL 的直接靶标，并表明当这些细胞接触融合蛋白时，I 型胶原蛋白的合成会大大加速。这些数据将 GST-RANKL 或其衍生物定位为潜在的骨合成代谢抗骨质疏松剂。因此，我们假设（1）GST-RANKL 通过不同的信号通路增强 OB 功能； (2) GST-RANKL通过转录和/或转录后诱导OB合成I型胶原蛋白； (3) GST-RANKL 预防和/或逆转骨质疏松症。因此，我们的具体目标是：（1）确定 GST-RANKL 增强 OB 功能的信号通路； (2)确定GST-RANKL诱导OB合成I型胶原蛋白的机制； (3) 确定 GST-RANKL 是否可以预防和/或逆转骨质疏松症。