Functional role and therapeutic potential of hedgehog signaling in tendon-to-bone repair

摘要 大约30%的美国成年人患有肌腱和韧带损伤，这种损伤经常发生在 插入部位到骨中(即凹陷)，不会自发愈合。生长和发育研究已经 已证明刺猬(HH)信号在驱动带状突触形成中起关键作用，但它在成体中的作用 齿槽修复在很大程度上是未知的。带状突起的形成包括锚定胶原纤维，合成 富含蛋白多糖的纤维软骨，并使其矿化。HH促进这种纤维软骨的形成。 不幸的是，在传统的肌腱到骨骼修复中研究这一途径一直是一个挑战，因为 修复模型不能充分地将胶原纤维固定在骨骼上，更不用说产生纤维软骨区了。 相反，韧带重建，即通过骨隧道放置肌腱移植物，可以产生带状韧带。 附属品。因此，韧带重建模式，如前十字韧带重建模式 在本应用中提出的，可用于研究调节带状肌腱到骨的机制 在成人身上修复。这项提案将通过针对刺猬途径来解决这一知识缺口。 新型前交叉韧带重建后肌腱-骨修复的遗传学和药理学研究 转基因小鼠模型。我们将确定Hedgehog通路在修复的特定阶段的作用 祖细胞库的扩大对带状体内纤维软骨和骨的产生的反应 隧道融合过程中的肌腱到骨的附着物。通过调节通路 从药理学上讲，我们将确定这一途径以翻译方式靶向的可能性 可能会在未来带来新的治疗方法。我们的中心假设是，HH途径是一个关键的积极因素 成人带状突触形成的调节器，因此刺激该通路将改善肌腱- 去骨修复。

Summary Approximately 30% of U.S. adults suffer from tendon and ligament injuries, which frequently occur near insertion sites into bone (i.e., entheses) and do not spontaneously heal. Growth and development studies have demonstrated a critical role for hedgehog (Hh) signaling in driving zonal enthesis formation but it's role in adult enthesis repair is largely unknown. Zonal enthesis formation involves anchoring collagen fibers, synthesizing proteoglycan-rich fibrocartilage, and mineralizing this fibrocartilage. Hh promotes this fibrocartilage formation. Unfortunately, studying this pathway in traditional tendon-to-bone repair has been a challenge since these repair models do not sufficiently anchor collagen fibers to bone, much less produce zones of fibrocartilage. Conversely, ligament reconstructions, where a tendon graft is placed through bone tunnels, can produce zonal attachments. Therefore, ligament reconstruction models, such as the anterior cruciate reconstruction model proposed in this application, can be employed to study the mechanisms that regulate zonal tendon-to-bone repair in the adult. This proposal will address this gap in knowledge by targeting the hedgehog pathway genetically and pharmacologically during tendon-to-bone repair following ACL reconstruction in novel transgenic mouse models. We will define the roles of the hedgehog pathway in specific stages of the repair response from the expansion of the progenitor pool to production of fibrocartilage and bone within zonal tendon-to-bone attachments during the tunnel integration process. By modulating the pathway pharmacologically, we will determine the potential for this pathway to be targeted in a translational fashion that could lead to novel therapies in the future. Our central hypothesis is that the Hh pathway is a critical positive regulator of zonal enthesis formation in the adult and therefore stimulation of the pathway will improve tendon- to-bone repair.