FAM13A as potential therapeutic target in modulating TGF-beta-induced airway tissue remodeling in COPD.

Abstract

Genome-wide association studies have shown that a gene variant in the Family with Sequence Similarity 13, Member A (FAM13A) is strongly associated with reduced lung function and the appearance of respiratory symptoms in patients with Chronic Obstructive Pulmonary Disease (COPD). A key player in smoking-induced tissue injury and airway remodeling is the transforming growth factor β1 (TGFβ1). To determine the role of FAM13A in TGFβ1 signaling, FAM13A-/- airway epithelial cells were generated using CRISPR-Cas9, while over-expression of FAM13A was achieved using lipid nanoparticles. Wildtype (WT) and FAM13A-/- cells were treated with TGFβ1, followed by gene and/or protein expression analyses. FAM13A-/- cells augmented TGFβ1-induced increase in COL1A1 and MMP2 expression compared to WT cells. This effect was mediated by an increase in CTNNB1 expression in FAM13A-/- cells compared to WT cells after TGFβ1 treatment. FAM13A over-expression was partially protective from TGFβ1-induced COL1A1 expression. Finally, we showed that airway epithelial-specific FAM13A protein expression is significantly increased in patients with severe COPD compared to control non-smokers, and negatively correlated with lung function. In contrast, β-catenin (CTNNB1), which has previously been linked to be regulated by FAM13A, is decreased in the airway epithelium of smokers with COPD compared to non-COPD subjects. Together, our data showed that FAM13A may be protective from TGFβ1-induced fibrotic response in the airway epithelium via sequestering CTNNB1 from its regulation on downstream targets. Therapeutic increase in FAM13A expression in the airway epithelium of smokers at risk for COPD, and those with mild COPD, may reduce the extent of airway tissue remodeling.