RANK Ligand is a Bone Anabolic Agent

描述(申请人提供)：迄今为止，骨质疏松症的治疗依赖于雌激素和双膦酸类等抗吸收药物。虽然这些药物经常延缓进行性骨质丢失，但它们在逆转已建立的骨质疏松损害方面并不有效，通常也不能治愈已经患有这种疾病的患者。甲状旁腺激素作为一种潜在的临床骨合成药物的显著效果强调了一种假说，即骨骼质量的大幅增加需要刺激骨形成。因此，识别促进全身成骨的分子是抗骨质疏松研究的重点。我们已经做出了令人惊讶的观察，关键的破骨细胞因子RANKL(RANKL)，当作为GST融合蛋白皮下注射时，是一种有效的骨合成代谢因子。这种化合物极大地促进了成骨细胞的形成，并在一周内刺激了活跃的骨形成，如放射学、组织学和密度计量学所检测到的那样。重要的是，GST-RANKL在体内诱导成骨细胞(OB)数量增加25倍时，并不促进破骨细胞的形成。我们还证实了OBS及其前体是GST-RANKL的直接靶点，并表明当这些细胞暴露在融合蛋白中时，I型胶原的合成大大加速。这些数据将GST-RANKL或其衍生物定位为潜在的骨合成代谢、抗骨质疏松药物。因此，我们假设(1)GST-RANKL通过不同的信号通路增强OBS的功能；(2)GST-RANKL在转录和/或转录后诱导OBS合成I型胶原；(3)GST-RANKL预防和/或逆转骨质疏松。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OBS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.