RANK Ligand is a Bone Anabolic Agent

描述（由申请人提供）：迄今为止，骨质减少性疾病的治疗依赖于抗吸收药物，如雌激素和双膦酸盐。虽然这些药物通常延缓进行性骨丢失，但它们不能有效逆转已建立的骨质疏松性病变，也不能典型地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药物的显著作用强调了骨骼质量的实质性增强需要刺激骨形成的假设。因此，鉴定促进全身性成骨的分子是抗骨质疏松研究的主要焦点。我们已经做出了令人惊讶的观察，即关键的破骨细胞生成细胞因子RANK配体（RANKL），当作为GST融合蛋白皮下给药时，是一种有效的骨合成代谢剂。该化合物显著增强成骨细胞生成，并在一周内刺激旺盛的骨形成，如放射学、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）数量增加多达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的直接靶点，并表明当这些细胞暴露于融合蛋白时，I型胶原蛋白的合成大大加速。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在转录和/或转录后诱导OB合成I型胶原;（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型胶原的机制;（3）确定GST-RANKL是否预防和/或逆转骨质疏松症。

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.