Osteogenesis imperfecta (OI), or brittle bone disease, is a rare congenital disorder characterized by bone fragility and increased fracture incidence mainly due to mutations in type I collagen or genes associated with collagen synthesis. Genetic and allelic heterogeneity underlie the phenotypic spectrum of OI yet all forms commonly feature early mortality stemming from pulmonary complications, the molecular cause for which has not been resolved. Using single-cell RNA sequencing (scRNAseq), we identified novel molecular and cellular mechanisms underlying the lung abnormalities observed in our Col1a1 Aga2/+ ( Aga2 ) mouse, which recapitulates a moderate form of OI. Pulmonary tissues in OI models have consistently displayed a histological emphysematous phenotype, however the origin of this and the effect on lung cell development and function remains unknown. Using scRNAseq data derived from young and adult Aga2 lungs, we found significantly increased AT2 to AT1 cell transition (cells necessary for alveolar structure and gas exchange) in young Aga2 mice but decreased AT2 cell differentiation in adults. Further, adult Aga2 lungs show increased fibroblast activation and differentiation. Finally, our scRNAseq analysis revealed a chronic inflammation phenotype in the Aga2 lung with increased neutrophil and monocyte numbers, IL1B and TNF pathway activation, NOD-like receptor signaling activation, and expression of the NLRP3 inflammasome. Most importantly, we saw a significant decrease in the expression of Scgb1a1 in immune, epithelial, and fibroblast cells. Decreased expression of Scgb1a1 is associated with multiple lung diseases such as emphysema, chronic obstructive pulmonary disease (COPD), and asthma and has become an important therapeutic target for chronic lung inflammation. Clinical treatments specific to pulmonary complications in OI are non-existent and our results reveal that chronic inflammation could be a target to prevent the pulmonary insufficiency and early mortality observed in OI patients.
Zieba et al. (Wed,) studied this question.