What Causes Respiratory Problems in Osteogenesis Imperfecta?

Osteogenesis imperfecta (OI), or brittle bone disease, has long been understood as a condition that primarily affects skeletal health. But recent research led by Roy Morello, PhD, a professor in the Department of Physiology and Cell Biology at the University of Arkansas for Medical Sciences, is expanding the understanding of OI’s broader impact, specifically on respiratory function.

In an interview featured in the first issue of The Respiratory Report, a quarterly pulmonology research newsletter powered by the American Lung Association Research Foundation, Morello detailed his team’s research into the effects of OI on the lungs, noting that patients with OI are often affected by respiratory complications.

“Osteogenesis imperfecta can cause severe respiratory distress at birth and also in adulthood,” Morello said. “Patients with OI can often suffer from decreased pulmonary function and are also more vulnerable to diseases such as pneumonia.”

In collaboration with pulmonologist John Carroll, MD, at Arkansas Children’s Hospital, Morello’s research initially focused on lung tissue from three different mouse models of OI. Their analysis revealed structural changes in the lung tissue that mirrored conditions like emphysema.

“We found significant changes in the lung parenchyma of these mice, which were reminiscent of emphysema with larger alveolar air spaces and a reduced number of alveoli,” Morello said. These structural differences were accompanied by functional alterations in respiratory mechanics in the mice, indicating that OI directly impacts lung health beyond its skeletal effects.

Morello’s team then developed a specialized mouse model to examine the direct impact of type I collagen mutations on the lungs, independent of the skeletal system.

“We developed this new model where we could then induce a nasty, severe OI mutation in type I collagen, just in the lung, but not in the skeleton,” he explained. This allowed the team to focus solely on lung-specific effects without the complicating factor of skeletal deformities.

Their findings showed that the severity of lung impairment was reduced when the mutation was limited to the lungs.

“Interestingly, when you express the mutation just in the lung, the phenotype was much less severe,” Morello said. However, the team still observed residual abnormalities in respiratory function. “The respiratory mechanics still suggested that some of the parameters were still altered, indicating that there were still some intrinsic alterations at the level of the distal alveolar airways.”

The ongoing research includes detailed analysis of the lung tissue through single-cell RNA sequencing to identify the molecular and cellular changes involved.

“We have now performed the single-cell RNA sequencing on a mouse model of osteogenesis imperfecta and are now zeroing in on changes that we see impacting certain fibroblastic populations, which are the cells producing type I collagen in the lung,” Morello said.

The results of this research indicate that while skeletal abnormalities in OI contribute to respiratory issues, there may also be lung-specific mechanisms that affect pulmonary function. As the study progresses, the research could lead to a more comprehensive approach to managing OI, potentially emphasizing the importance of monitoring lung health in affected patients.

To learn more about Morello’s research, read his contribution to the first issue of The Respiratory Report here:

Elucidating the Role of Type I Collagen Mutations on Respiratory Function in Osteogenesis Imperfecta