Genetic determinants of endoplasmic reticulum stress in OI and its consequences on cellular receptors - PROJECT SUMMARY/ABSTRACT Osteogenesis imperfecta (OI) is among the most common osteochondrodysplasias. It is genetically heterogenous, resulting from mutations in 22 different genes. Regardless of the genotype, the disorder is characterized by brittle bones with recurrent fractures due to impaired bone quantity and quality. OI is also phenotypically heterogeneous with mild, moderate, severe, and perinatal lethal forms of disease. The incidence is estimated at 1/20,000 births and around 20,000 to 50,000 Americans have OI.1,2 About 85% of OI cases result from dominant mutations in COL1A1 or COL1A2 which encode the α1 and α2 chains of type I collagen, the major protein in bone.3 Rare forms of OI are from mutations in other genes involved in type I collagen synthesis, modification, trafficking, or osteoblast function.4 In the United States, there are no therapeutic agents labeled for use in OI. OI is typically treated with bisphosphonates and supplemented with calcium and vitamin D.3,5 Bisphosphonates are anti-resorptive agents that induce osteoclast apoptosis and are indicated for use in osteoporosis and diseases with pathologic bone resorption.6 While bisphosphonates have been effective in increasing bone mineral density in OI, their effect on fracture risk is uncertain and may cause OI bone to become even more brittle.7 This uncertainty, combined with our growing knowledge of OI pathophysiology, have driven the field to search for alternative treatment strategies. Intermittent parathyroid hormone, anti-sclerostin therapy, and anti-TGFβ therapy have all been clinically tested in patients with OI. In each study, only a subset of patients exhibited a beneficial response. In OI, the mechanistic etiology of the variability in response to treatment is not understood and significantly affects patient care. I hypothesize this response variability in OI results, in part, from a genotype dependent accumulation of misfolded type I collagen. Type I collagen is co-translationally inserted into the endoplasmic reticulum (ER) lumen as procollagen alpha chains. There, they are post-translationally modified and fold before exiting the ER. In OI due to glycine substitutions or splicing mutations, misfolded type I procollagen accumulates in the ER lumen of osteoblasts producing ER stress. In addition to collagen, many other cellular products are processed through the ER including transmembrane receptors, extracellular matrix components, and secreted ligands. Under ER stress, the cell may not be able to synthesize and process normal levels of these cellular products . I will test the hypothesis that ER stress in OI is genotype dependent and leads to dysregulated osteo- progenitor/osteoblast signaling function due to receptor/ligand signaling cascades. This proposal will establish that ER stress is more than a cellular response – it is clinically important and genotype dependent in OI. It also provides preclinical data for a new treatment strategy for OI and adds to the growing view that the OI phenotype is not simply due to a structurally defective extracellular matrix.
