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 a1 and a2 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-TGFß
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.
