Osteogenesis Imperfecta (OI) or brittle bone disease is the most common primary osteodysplasia of the skeleton. In 2006, our group and collaborators defined the mechanistic basis of a unique post-translational modification of fibrillar collagens, i.e., 3-prolyl-hydroxylation, to involve a trimeric complex composed of Cartilage Associated Protein (CRTAP), Prolyl hydroxylase 1 (P3H1 encoded by LEPRE1), and Cyclophiliin B (CYPB) also known as peptidy-prolyl isomerase B (encoded by PPIB). We and others have since demonstrated that mutations in these genes account for the majority of remaining cases that constitute a recessively inherited class of OI. Biochemically, we know that mutations in these genes can be associated with a panoply of biochemical and cell biological changes: 1) intracellular posttranslational overmodification of collagen, 2) dilatation and disorganization of cellular organelles including the rough endoplasmic reticulum (rER), 3) alteration in secretion and fibrillogenesis, 4) dysregulation of extracellular collagen processing including propeptide cleavage and fibril crosslinking, and 5) altered rates of osteoid deposition and matrix mineralization. Still, we do not know how these alterations contribute to the clinical picture of OI. Importantly, the fact that we cannot easily distinguish the clinical features caused by diverse genetic mutations and biochemical alterations supports the hypothesis that there are underiying common mechanisms of cellular and tissue dysfunction that lead to brittle bone. In this project, we propose to dissect the two biochemical activities of the 3-prolyl hydroxylase complex, i.e., 3-prolyl-hydroxylation of fibrillar collagens vs. chaperone function of collagen, to determine whether alterations in matrix cell signaling may be a common mechanism in the pathogenesis of recessive OI, and to identify novel genetic causes of OI, specifically types V and VI.

Public Health Relevance

By studying how mutations that affect a group of genes that modify collagen function translate into bone fragility in osteogenesis imperfecta, we hope to identify novel therapies and improved diagnostic tools.

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Baylor College of Medicine
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Lietman, Caressa D; Marom, Ronit; Munivez, Elda et al. (2015) A transgenic mouse model of OI type V supports a neomorphic mechanism of the IFITM5 mutation. J Bone Miner Res 30:489-98
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