Enhancing Notch Activation for Improved Bone Regeneration
Abstract
Over one-quarter of all military personnel who are injured in combat suffer bone injuries to their arms, legs, or face. This is because body armor and helmets protect the torso and the head, but the limbs and face are left unprotected. Civilians sustain similar injuries in motor vehicle collisions, falls, and after gunshot injuries. The goal of bone repair is to have the body replace or restore lost bone in as rapid and robust a manner as possible. While bone usually heals without complication, those injuries that have a profound loss of bone do not heal well and require extensive revision surgeries and then about 10% of patients do not heal at all (called non-unions) or have slow/delayed healing. Over the past 20 years, knowledge of bone healing has dramatically increased with the discovery and clinical use of growth factors (proteins that stimulate tissue formation) that directly induce the formation of cells that form bone. Indeed, commercially available growth factors, named bone morphogenetic proteins (BMP), have been used for the past 10 years as adjuncts to promote bone healing. However, there is a lack of efficacy with BMP and safety concerns; thus, there is a clear need to develop new methods to increase bone formation The research proposed in this application is an expansion of a project funded in 2009 by the Peer Reviewed Orthopaedic Research Program. For the initial award, we sought to better understand the role of a unique growth factor signaling pathway in the regulation of bone formation. This pathway is termed "Notch signaling." Our results from the previous funding period show that Notch is very important in bone formation and regeneration and that activation of Notch can increase the number and activity of bone forming cells, termed osteoblasts. In particular, our work has most thoroughly characterized the Notch signaling ligand Jagged1 as a direct osteoblast inducer. Notch ligands have properties that make them safe and more specific for increasing bone regeneration. The work described in the new application will determine the ideal therapeutic molecule that can be delivered to induce osteoblast differentiation. Jagged1 will be compared to ligand family members. As well, we will use novel structure-based computational modeling to predict new non-protein based small molecules that can induce Notch signaling. Next, comparative information concerning Notch dosing and safety relative to BMP will be obtained, and we will determine whether Notch can synergize with BMP to induce bone formation and thereby improve the safety profile for BMP. Finally, we will show the efficacy of local induction of Notch signaling by the Jagged1 ligand to promote healing in two different rat bone injury models, a femoral defect model and calvarial defect model. Our ultimate goal is to develop an easy-to-use, straight-forward construct (based on a Food and Drug Administration-approved carrier) that activates Notch signaling in osteoblast progenitors when placed locally at a bone injury site by an orthopaedic surgeon. We believe that if we are successful in this 3-year period at showing the utility of Notch signaling activation to promote bone repair in two rat models, then a large animal (for instance, sheep or pig) preclinical model could be developed and tested within another 2 years. This timeline would then suggest that a viable therapeutic could be developed within 5 years to help Soldiers on the battlefield with fractures and bone defects. We believe that any risks of a therapeutic based on Notch delivery on a biodegradable biomaterial are quite low. The Jagged1 will only be active for a short time period, and the delivery carrier being pursued is a simple collagen sponge, already used clinically to deliver BMP and it is fully degradable. A collagen sponge is easy to manipulate; thus, clinical applications can use it to fill large bone defects or to wrap around injured bones to accelerate healing an
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510689
Entities
People
- Kurt D. Hankenson
Organizations
- Michigan State University
- United States Army