The work in this article summarizes findings from our group on key biochemical cues that govern the formation and repair of tendons and ligaments. Specifically, we summarize the journey that started with a serendipitous discovery that is now being translated into novel therapies to improve tendon-to-bone repair outcomes. This journey began with the discovery that the Hedgehog (Hh) signaling pathway was expressed within the enthesis during development and that its primary role was to promote fibrocartilage production and maturation. Next, we developed an anterior cruciate ligament reconstruction model in novel transgenic mice that allowed us to discover that the Hh pathway promotes fibrocartilaginous tendon-to-bone attachments during the integration process. In addition, we established that the coordinated stages of zonal tendon-to-bone integration after anterior cruciate ligament reconstruction were comparable with the stages required for enthesis formation during development. Now that we have demonstrated that the Hh pathway is a potent therapeutic target, we are currently advancing these findings to develop drug delivery systems to improve tendon-to-bone repair. Ultimately, our group aims to establish key mechanisms that govern tendon and ligament formation that can be leveraged for novel regenerative therapies to improve clinical care.
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