Dissecting primary versus secondary effects of osteogenesis imperfecta on abnormal lung development and function.

Skeletal dysplasias, including osteogenesis imperfecta (OI), can lead to perinatal respiratory distress and failure with limited therapeutic options. OI is mostly caused by dominant mutations in either COL1A1 or COL1A2 genes and in addition to its dramatic impact on the skeleton, it affects other organs, including the lung with respiratory complications being a leading cause of mortality in patients with OI. In various mouse models of OI, we and others have shown impaired alveolar formation resulting in alveolar simplification, and functional changes in respiratory mechanics. However, assessing the contribution of OI-causing genetic variants to pulmonary function independent of the congenital and progressive skeletal defects caused by OI has been impossible. To address this issue, we generated a new mouse model that expresses a severe OI-causing Col1a1 glycine substitution (p.Gly1146Arg) only in the lungs, allowing us to study its effects on lung morphology and function in the context of a healthy rib cage and compare them with the effects of the global expression of this variant at 3 months of age. We found that the global expression of the Col1a1 p.Gly1146Arg variant resulted in distal lung parenchyma defects and alterations in respiratory mechanics, similar to those described earlier in other mouse models of OI. Conversely, the expression of the variant in lungs only, beginning in utero, caused a milder phenotype without significant lung parenchyma alterations and with normal respiratory mechanics parameters but with persistent findings of reduced K and V10_TLC, indicating a reduced compliance of the respiratory system. Our findings indicate that skeletal defects, perhaps concomitantly with respiratory muscles and tendon defects, play a critical role in the proper alveolar development/formation and respiratory function in OI. Future and ongoing studies will try to address further cellular and molecular changes caused by defective expression of type I collagen in the lung.