IDENTIFICATION OF ANABOLIC AGENTS FOR BONE GROWTH

骨质疏松症是一种骨质过少的疾病。 虽然有有效的骨质疏松症再吸收抑制剂（二膦酸盐，雌激素和降钙素），这些药物不会导致骨量的实质性增加。 因此，对于已确诊骨质疏松症的患者，需要合成代谢治疗剂。 我们已经开发了一种基于细胞的筛选试验，通过该试验，我们可以鉴定在已建立的骨质疏松症啮齿动物模型中增加骨量的小分子量化合物。 我们的具体目的是1）确认所选生物活性化合物在体内刺激骨形成的能力的效果，2）在卵巢切除大鼠（骨质疏松症的动物模型）中测试该化合物在全身给药后增强骨形成的能力的效果，和3）在骨再生缺陷模型中测试全身给药该所选化合物的效果。 这些化合物不仅是骨质疏松症的潜在治疗方法，而且也是其他骨丢失原因如节段性骨缺损、牙周病和骨折修复的潜在治疗方法。建议的商业应用骨质疏松症是一个主要的公共卫生问题，延迟骨折修复是残疾的主要原因。 需要治疗来增加骨的形成并增加丢失的骨。 对于这些情况，理想的药物是口服的，并且可以通过增加骨生长因子的内源性产生来刺激骨的形成。 这个项目的目的是表征一个这样的化合物，我们已经确定。

Osteoporosis is the disorder of too little bone. Although there are effective resorption inhibitors for osteoporosis (bisphosphonates, estrogen and calcitonin), these drugs do not cause substantial increases in bone mass. For patients with established osteoporosis, there is thus a need for anabolic therapeutic agents. We have developed a cell-based screening assay with which we can identify small molecular weight compounds which increase bone mass in rodent models of established osteoporosis. Our specific aims now are to 1) confirm the effects of a selected biologically active compound for its capacity to stimulate bone formation in vivo, 2) test the effects of this compound for its capacity to enhance bone formation following systemic administration in ovariectomized rats (an animal model of osteoporosis), and 3) test the effects of this selected compound administered systemically in a defect model of bone regeneration. Such compounds will be potential therapies not just for osteoporosis but also for other causes of bone loss such as segmental bone defects, periodontal disease and fracture repair. PROPOSED COMMERCIAL APPLICATION Osteoporosis is a major public health problem and a delayed fracture repair is a major cause of disability. Therapy is needed to increase the formation of bone and augment the bone that is lost. An ideal drug for these situations would be one that is orally available and could stimulate the formation of bone by increasing the endogenous production of bone growth factors. This project aims to characterize one such compound we have identified.