Procollagen Biosynthesis and Osteoblast Malfunction in the G610C Mouse Model of Osteogenesis Imperfecta
MetadataShow full item record
Osteogenesis imperfecta (OI) is a hereditary disease that disrupts bone formation and function resulting in skeletal deformities and fragile bones. OI is diagnosed based on clinical and radiological examination, with patient symptoms ranging in severity from relatively mild (increased incidence of fractures) to severe (low impact fractures, severe skeletal deformities) to lethal (respiratory insufficiency soon after birth). To date, mutations in over a dozen genes that cause OI have been identified, of which ~90% are autosomal dominant and ~10% are autosomal recessive. In 5-10% of clinical cases the mutations remain unknown. Mutations in type I collagen, the triple helical protein that makes up the fibrous organic scaffold (matrix) of bone, are responsible for over 80% of OI cases. Interestingly, OI severity in patients with the same collagen mutation is highly variable, suggesting it may be possible to find a treatment that does not require gene repair. Furthermore, as OI pathology shares features with other disorders such as common osteoporosis, studying this rare genetic disorder may unmask common molecular mechanisms and result in novel approaches to treatment of both disorders. Nevertheless, even the most basic mechanisms of OI pathophysiology are still poorly understood. The goal of the present study was to lay the foundation for understanding how malfunction of bone producing cells contributes to OI pathology with the aim of finding treatments that do not involve presently unrealistic gene repair. Specifically, we focused on characterizing how the most common OI mutations in collagen affect: (1) collagen synthesis in bone producing cells, (2) bone cell differentiation and function, and (3) bone formation in vivo. To answer these questions, we chose to use a recently developed mouse model of moderately severe OI that mimics the genetic defect and phenotype variability found in the largest known group of OI patients with the same mutation.