Distinct type I collagen alterations cause intrinsic lung and respiratory defects of variable severity in mouse models of osteogenesis imperfecta

Type I collagen alterations cause osteogenesis imperfecta (OI), a connective tissue disorder characterized by severe bone fragility. Patients with OI can suffer from significant pulmonary manifestations including severe respiratory distress in the neonatal period and a progressive decline in respiratory function in adulthood. We and others have shown intrinsic lung defects in some mouse models of OI. In this large study, we performed histological, histomorphometric, microcomputed tomography and invasive studies on oim/+, Col1a2(+/G610C), CrtapKO and oim/oim mice, mimicking mild to moderate to severe OI, with the overall goal of determining the extent of their pulmonary and respiratory mechanics defects and whether these defects correlate with the skeletal disease severity and affect each sex equally. Although with variable severity, OI lung histology consistently showed alveolar simplification with enlarged acinar airspace and reduced alveolar surface. Numerous respiratory mechanics parameters, including respiratory system resistance and elastance, tissue damping, inspiratory capacity, total lung capacity, and others, were significantly and similarly impacted in CrtapKO and oim/oim but not in oim/+ or Col1a2(+/G610C) compared to control mice. Our data indicate that the impact of type I collagen alterations and OI on lung morphology and function positively correlate with the severity of the extracellular matrix deficiency. Moreover, the respiratory defects were more pronounced in male compared to female mice. It will be important to determine whether our observations in mice translate to OI patients and to dissect the respective contribution of intrinsic lung defects vs. extrinsic skeletal defects to impaired lung function in OI.

Automated summary

Collagen alterations in osteogenesis imperfecta (OI) lead to severe bone fragility and can cause lung and respiratory function defects. This study investigated the extent of pulmonary and respiratory mechanics defects in mouse models of OI, and found a correlation between the severity of extracellular matrix deficiency and lung morphology and function. The respiratory defects were also more pronounced in male mice. Further research is needed to determine if these findings apply to OI patients and to understand the contribution of intrinsic lung defects and extrinsic skeletal defects to impaired lung function in OI.