Pharmacologic Activation of the Hypoxia Inducible Factor Pathway in Bone Healing

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DESCRIPTION (provided by applicant): Distraction osteogenesis is a powerful tool for limb reconstruction. However, frequent problems, obstacles and complications make application of the methods difficult for patients and physicians. Among these issues, delayed or failed bone healing can be particularly problematic, requiring prolonged external fixation and/or additional procedures. A key feature of distraction is the induction of angiogenesis. Prior studies have shown that hypoxia inducible factor (HIF), a key regulator of the response to altered oxygenation and promoter of angiogenesis, is strongly induced during distraction osteogenesis. Further, we have demonstrated that increased HIF activation in bone in a mouse model increases postnatal bone acquisition. In this proposal, we will test the hypothesis that increased activation of HIF pathway will alter bone healing in distraction osteogenesis. We will use pharmacologic intervention to block HIF degradation, resulting in increased HIF activation and increased activation of downstream targets influencing angiogenesis. In aim 1, we will evaluate pharmacologic agents for potential to increase HIF activation and upregulate downstream targets in vitro, and select the most promising for evaluation in vivo. In the second aim, the agents will be applied locally to the distraction zone in mice undergoing distraction osteogenesis of the tibia. We will examine the distracted bones histologically, radiographically and biomechanically. Also, a second experimental group will undergo distraction at a supraoptimal rate, a maneuver that leads to delayed or non healing, to test whether increased HIF activation can allow faster distraction or lead to healing of non-unions.