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吸收抑制剂（双膦酸盐、雌激素和降钙素），但这些药物不会导致骨量的显著增加。对于骨质疏松症患者，需要使用合成代谢治疗药物。我们已经开发了一种基于细胞的筛选试验，我们可以识别小分子量化合物，这些化合物可以增加骨质疏松症啮齿动物模型的骨量。我们现在的具体目标是1)确认一种选定的生物活性化合物在体内刺激骨形成的作用，2)测试该化合物在去卵巢大鼠（骨质疏松症动物模型）系统给药后增强骨形成的作用，以及3)测试该选定化合物在骨再生缺陷模型中系统给药的作用。这类化合物不仅是治疗骨质疏松症的潜在疗法，而且还可用于其他原因的骨质流失，如节段性骨缺损、牙周病和骨折修复。骨质疏松症是一个主要的公共健康问题，延迟骨折修复是导致残疾的主要原因。需要治疗来增加骨的形成和增加丢失的骨。对于这些情况，一种理想的药物是口服的，可以通过增加内源性骨生长因子的产生来刺激骨的形成。本项目旨在表征我们已经确定的一种这样的化合物。

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.