Regulation Of Pulmonary Fibrosis By Cd109 In A Murine Model
Maha Alsharqi, Liqin Xu, Meryem Blati, Anie Philip.
Mcgill University, Montreal, QC, Canada.
BACKGROUND: Transforming growth factor (TGF)-β is a pleiotropic cytokine that regulates a broad spectrum of biological processes. TGF-β signaling is transduced by the type I and type II TGF-β receptors. TGF-β co-receptors such as CD109 are known to strongly regulate TGF-β signaling in a variety of cell types. Scleroderma (SSc) is a connective tissue disease characterized by fibrosis of the skin and internal organs such as the lung. Although aberrant regulation of TGF-β signaling is known to play a key role in SSc, the significance CD109 function in pulmonary fibrosis in SSc is unknown.
METHODS: We examined the effect of CD109 deficiency on fibrotic responses in the lung and skin using CD109 knockout (KO) versus wild-type (WT) littermate mice. Lung and skin tissues were harvested from KO and WT mice. Collagen deposition and tissue architecture were examined histologically using H&E and Massonís trichrome staining. Extracellular matrix (ECM) protein expression was analyzed by immunohistochemistry, and by Western blot. Lung and skin fibroblasts were isolated from KO and WT mice and analyzed for TGF-β signaling by measuring phospho-Smad2/3 levels. Also, fibroblasts migration was analyzed using an in vitro wound healing assay.
RESULTS: Both lung and skin tissue from KO mice show markedly increased cellularity, collagen disorganization and expression of collagen type I, fibronectin, CTGF, and alpha smooth muscle actin, as compared to those from WT littermates (p<0.05 in all cases), with the lung exhibiting more dramatic increases than the skin. Furthermore, lung and skin fibroblasts from KO mice display significantly elevated phospho-Smad2/3 signaling and enhanced wound healing (migration) in vitro.
CONCLUSIONS: Our finding that CD109 deficiency results in markedly enhanced TGF-β signaling, fibrotic responses, cellularity and migration in the lung signify the importance of CD109 in ECM synthesis and homeostasis of the lung. As decreased CD109 function plays a critical role in increased fibrotic responses in the lung, CD109 may represent a molecular target for therapeutic intervention in pulmonary fibrosis in SSc.
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