Osteogenesis Imperfecta (OI) is one of the most common heritable disorders of connective tissue. It is characterized by brittle bones, and over the past four decades, the genetics of OI has taught us about the basic mechanisms of procollagen assembly, post-translational modification, secretion, fibril formation and matrix mineralization. In an accelerated phase of discovery over the past 9 years, the identification of new OI genes has further informed us about the determinants of bone quantity and quality during skeletal development and homeostasis. This Program Project Grant (PPG) began in 2010 and has significantly contributed to this rapidly evolving field. In 2006, we reported that mutations in CRTAP caused recessive forms of severe OI (types III and VII). CRTAP is part of a trimeric protein complex including P3H1 and CYB that together are required for prolyl-3-hydroxylation, a poorly understood post-translational modification of clade A fibrillar collagens (e.g., types I, II, and V collagen). We also identified additional type I procollagen binding proteins, FKBP10 and HSP47, as important components in procollagen assembly and trafficking. We and others have since discovered that mutations in the genes encoding these proteins also contribute to the expanding group of brittle bone disorders (BBDs). The overall goal of this PPG is to elucidate the mechanistic consequences of mutations in procollagen and its modification proteins on bone and to translate this into new targeted diagnostic and therapeutic approaches. In this PPG renewal application, we hypothesize that the brittle bone phenotype in OI is a developmental model of abnormal bone quality and quantity that broadly integrates 1) altered matrix-to-cell signaling defects leading to abnormal bone quantity and cellular function, with 2) altered strength, biochemical nature and intermolecular placement of collagen crosslinks leading to abnormal bone mineralization and quality. To test this hypothesis, we will combine mouse genetic modeling, cell based studies, state-of-the-art mass spectrometric analysis of collagen with continued human genetic gene discovery to elucidate basic mechanisms that will inform genotype-based therapy and diagnostic biomarkers. The PPG will leverage infrastructure housed within the Co-Investigators' programs. The PPG is composed of three projects, a Functional Genomics Core, and an Administrative Core. The projects will answer three important questions. Project 1: What are the downstream mechanisms in WNT1 forms of OI and how do mutations affect osteoblast, osteoclast, osteocyte, and matrix function? Project 2: How do mutations in the FKBP65/HSP47 & PLOD2 collagen chaperone complex affect bone development? Project 3: What are the phenotypic and clinical consequences of altered crosslinking in OI patients and mice with defects affecting procollagen modification and trafficking with regard to bone?
This proposal addresses the basic mechanisms that cause Osteogenesis Imperfecta (OI) the most common of the brittle bone disorders. By combining the study of signaling, altered collagen matrix production, and biochemical cross-linking, we hope to understand the major determinants of bone quantity and quality. In so doing, we aim to develop mechanistic-based, genotype-specific therapeutic and prognostic approaches to OI.
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