In this, Project 3, of an interinstitutional collaboration our goal is to understand the molecular mechanisms that underlie the brittle bone that is the hallmark of the heritable disorder, osteogenesis imperfecta (OI). Our focus is on the collagen matrix of bone which determines the material toughness of the tissue and the template in which the mineral is deposited during bone formation. During the first 5-year period in collaboration with Projects 1 and 2 we have discovered, by analyzing bone and other tissue collagens from mouse models and human OI cases, a strong interplay between the mechanisms of collagen prolyl 3-hydroxylation and lysyl hydroxylation in the control of collagen cross-linking quality and predictably bone strength. Going forward we plan to define the molecular basis for this. Our methods remain focused on using analytical tandem mass spectrometry as a tool to interrogate and compare abnormal collagen structures from various genetic forms of OI. The significance extends to a better understanding of brittle bone more generally with potential for new therapeutic molecular targets and diagnostic methods.
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