Profibrotic role of WNT10A via TGF-β signaling in idiopathic pulmonary fibrosis

Background: WNT/beta-catenin signaling plays an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF); however, the role of WNT10A via transforming growth factor (TGF)-beta signaling remains unclear. Methods: We evaluated the expression of WNT10A and TGF-beta in bleomycin (BLM)-treated mice and the interactions between TGF-beta or BLM and WNT10A in vitro. Additionally, we investigated IPF patients who underwent video-assisted thoracoscopic surgery to determine whether the WNT10A expression is related to the survival. Results: Increased WNT10A and TGF-beta expressions were noted in the BLM-treated mice. Real-time PCR and luciferase reporter assays demonstrated the levels of WNT10A and collagen in the fibroblasts cells to increase after TGF-beta administration. Conversely, WNT10A siRNA treatment inhibited the synthesis of collagen in the transfected fibroblasts cells. A Kaplan-Meier survival analysis demonstrated a tendency toward a poor survival among the IPF patients with a WNT10A-positive expression compared to those with a negative expression (Hazard ratio 5.351, 95 % CI 1.703-16.82; p = 0.0041). An overexpression of WNT10A was found to be significantly predictive of an acute exacerbation of IPF (AE-IPF) (Odds ratio 13.69, 95 % CI 1.728-108.5; p = 0.013). Conclusions: WNT10A plays an important role in the pathogenesis of IPF via TGF-beta activation and it may also be a sensitive predictor for the onset of an AE-IPF.