RANK Ligand is a Bone Anabolic Agent

RANK Ligand 是一种骨合成代谢剂

• 批准号: 6508327
• 负责人: Steven L Teitelbaum
• 金额: $ 34.91万
• 依托单位: BARNES-JEWISH HOSPITAL
• 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 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6508327
• 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）：对骨质减少性疾病的治疗已依赖于抗敏化药物（例如雌激素和双膦酸盐）。尽管这些药物通常会阻碍进行性骨质流失，但它们在逆转已建立的骨质疏松病变方面并不有效，也没有通常能够治愈已经患有该疾病的患者。甲状旁腺激素作为潜在的临床骨合成代谢药物的戏剧性作用强调了骨骼质量大大增强需要刺激骨形成的假设。因此，促进全身性成骨的分子的鉴定是抗骨质疏松研究的主要重点。我们已经做出了一个令人惊讶的观察，即关键的破骨细胞因子rank配体（RANKL）当皮下施用作为GST融合蛋白时，是一种有效的骨合代剂。这种化合物大大增强了成骨细胞生成，并在一周内刺激了充满活力的骨骼形成，如射线照相，组织学和密度法上所检测到的那样。重要的是，剂量的GST-量克重诱导成骨细胞（OB）数量增加了25倍，不会促进体内骨质质发生。我们还确定，OBS及其前体是GST-秩的直接靶标，并且表明，当这些细胞暴露于融合蛋白时，这些细胞I型胶原蛋白合成会大大加速。这些数据位置GST-rankl或其衍生物是潜在的骨合成代谢，抗骨质疏松剂。因此，我们假设（1）GST-rankl通过不同的信号途径增强了观察功能； （2）转录和/或转录后的GST量表，通过obs诱导I型胶原蛋白合成； （3）GST-rankl可防止和/或逆转骨质疏松症。因此，我们的具体目的是：（1）确定GST-RANKL增强OB功能的信号途径； （2）确定GST-秩型通过obs诱导I型胶原蛋白I型合成的机制； （3）确定GST-rankl是否阻止和/或逆转骨质疏松症。