The Effects of Systemic Hedgehog Pathway Modulation on Fracture Healing

 描述(由申请人提供)：许多患者和损伤特征损害了骨再生的生物学，并导致临床骨折愈合延迟。这是一个相对常见的问题，发生在骨不连、脊柱融合失败和老年患者等临床情况下，所有这些都会导致患者发病率和社会负担。骨折愈合通常是通过一系列复杂的分子事件发生的。刺猬的分子途径与骨形成和骨愈合直接相关。尽管几乎没有确切的数据可用，但初步研究表明，刺猬可能是一个强大的潜在药理靶点，以促进骨形成。在这项研究中，我们将评估口服全身性药物改变刺猬途径的活性。我们将使用正常的小鼠股骨骨折模型和修复骨折能力受损的小鼠。该方法旨在为Hedgehog通路对骨折愈合的调控提供一种机制分析。如果建议的研究成功，这将是一个概念的证明，即可以通过激活或抑制Hedgehog通路来上调或下调骨折愈合，并将为进一步开发针对Hedgehog途径的药物干预以促进骨折愈合奠定基础。然后，可以采用几种潜在的未来战略。首先，可以对刺猬激活和骨折之间的联系进行更完整的路径分析。一些需要解决的问题包括：这是对骨软骨系细胞的直接影响，还是通过增加血管生成的间接影响，或者两者兼而有之？在骨折愈合的哪个阶段，刺猬最活跃？下一步，可以对激活刺猬途径的其他小分子进行彻底的探索。可以对HH-Ag1.5和其他有前景的疗法进行理想的剂量和安全性评估。总体而言，拟议的一系列实验可能是开发用于骨折愈合刺激的新生物靶点的重要第一步。

 DESCRIPTION (provided by applicant): Many patient and injury characteristics impair the biology of bone regeneration and lead to delayed clinical fracture healing. This is a relatively common problem, occurring in non-unions, spinal fusion failures, and in elderly patients, among other clinical situations, all of which lead to substantial patient morbidity and societal burden. Fracture healing normally occurs by a series of complex molecular events. The hedgehog molecular pathway is directly related to bone formation and bone healing. Although little definitive data is available, preliminary studies indicate that hedgehog may be a powerful potential pharmacologic target to enhance bone formation. In this study, we will evaluate oral systemic agents that alter the activity of the hedgehog pathway. We will use a normal mouse femur fracture model and mice with an impaired ability to heal fractures. This approach is designed to provide a mechanistic analysis of hedgehog pathway modulation on fracture healing. If the proposed studies are successful, this would be a proof-of-concept that fracture healing can be upregulated or down-regulated by activation or inhibition of the hedgehog pathway, and would be grounds for further development of pharmacologic interventions that target the hedgehog pathway to enhance fracture healing. Several potential future strategies could then be employed. First, a more complete pathway analysis of the link between hedgehog activation and fracture could be performed. Some questions to be addressed include: Is this a direct effect on cells of the osteochondral lineage, or an indirect effect via increased angiogenesis, or both? At what stage of fracture healing is hedgehog most active? Next, a thorough exploration for other small molecules that activate the hedgehog pathway could be performed. Ideal dosing and safety profiles could be evaluated for Hh-Ag1.5 and other promising therapeutics. Overall, the proposed series of experiments could be an important first step in the development of a novel biological target for fracture healing stimulation.