? DESCRIPTION (provided by applicant): The physiological repair of severe bone fractures in patients often results in incomplete bone closure. Bmp-2 has been used clinically to improve bone repair. However even with the use of Bmp-2, a strong inducer of osteoblast differentiation, obtaining complete bone closure is still a problem. Moreover, current treatments have led to multiple medical complications due to supra-physiological levels of Bmp-2 required to promote repair bone. Therefore there is a need to identify new candidates that can improve Bmp-2 efficacy in bone healing. High concentrations of Bmp-2 are required in part because of our limited understanding of the role the extracellular matrix (ECM) plays in Bmp-2 signaling during bone repair. Given the relatively large number ECM proteins known to negatively regulate Bmp-2-mediated bone formation it is important to identify positive ECM modulators of Bmp-2 signaling. We have recently reported that the ECM protein, Fibulin-1 (Fbln1) is a positive modulator of bone formation that binds Bmp-2 and acts to promote osteoblast differentiation. In order to further our mechanistic understanding of Fbln1 in bone formation and address the role of Fbln1 in bone regeneration we have proposed two specific aims 1) Define the region(s) within Fibulin-1 responsible for Bmp-2-mediated induction of Osterix and Bmp-2 binding 2) Determine if Fibulin-1 is required for repair of critical size calvarial defects.
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