Mechanisms of WNT Signaling In Bone

 描述（由申请人提供）：Wnt信号传导已成为开发新型骨合成代谢剂的主要靶途径。虽然有前途的治疗方法已经进入临床试验，我们对Wnt信号如何促进骨愈合的理解仍然不完整。尽管如此，对机制的基本理解对于下一代疗法的合理设计至关重要。我们以前已经发现，Wnt信号在成骨细胞分化过程中重新编程细胞代谢。特别是，Wnt刺激有氧糖酵解和β-氨基丁酸解。我们已经进一步证明，增加β-氨基糖苷酶满足成骨细胞的能量和生物合成的需要。此外，用小分子重定向糖酵解远离乳酸盐的产生减少了Wnt诱导的骨形成。然而，它仍然是未知的糖酵解开关有利于乳酸生产有助于骨愈合响应Wnt。在这里，我们测试的中心假设，Wnt诱导的有氧糖酵解促进骨形成，通过刺激β-内酰胺酶。我们在三个具体目标中检验这一假设。目的1检测Ldha基因缺失对Lrp 5基因突变引起的小鼠骨质疏松症的影响。目的2：明确骨移植和原代细胞培养中糖酵解和β-氨基醇解之间的关系。最后，在目标3中，我们将确定Ldha过表达在听骨植入物模型和转基因小鼠中促进骨形成的功效。该提案的成功完成预计将为开发骨增强药物铺平新的道路。

 DESCRIPTION (provided by applicant): Wnt signaling has emerged as a major target pathway for developing novel bone anabolic agents. Although promising therapeutics has entered clinical trials, our understanding about how Wnt signaling promotes bone anabolism remains incomplete. Nonetheless, a fundamental understanding of the mechanism is critical for rational design of the next generation of therapies. We have previously discovered that Wnt signaling reprograms cellular metabolism during osteoblast differentiation. In particular, Wnt stimulates both aerobic glycolysis and glutaminolysis. We have further demonstrated that the increase in glutaminolysis fulfills both energetic and biosynthetic needs of osteoblasts. Moreover, redirecting glycolysis away from lactate production with a small molecule diminishes Wnt-induced bone formation. However, it remains unknown how the glycolytic switch favoring lactate production contributes to bone anabolism in response to Wnt. Here we test the central hypothesis that Wnt-induced aerobic glycolysis promotes bone formation through stimulation of glutaminolysis. We test the hypothesis in three specific aims. Aim 1 genetically tests the effect of Ldha deletion on osteosclerosis caused by a mutation of Lrp5 in mice. Aim 2 specifically examines the relationship between glycolysis and glutaminolysis in both bone explants and primary cell cultures. Finally, in Aim 3 we will determine the efficacy of Ldha overexpression in promoting bone formation in both an ossicle implant model and transgenic mice. Successful completion of the proposal is expected to pave a new avenue for developing bone-enhancing drugs.