Silicosis is an
occupational disease caused by inhalation of
silica dust, which is hallmarked by progressive
pulmonary fibrosis associated with poor prognosis. Wnt/β-
catenin signaling is implicated in the development of
fibrosis and is a therapeutic target for fibrotic diseases. Previous clinical studies of patients with
pneumoconiosis, including
silicosis, revealed an increased concentration of circulating WNT3A and DKK1
proteins and inflammatory cells in bronchoalveolar lavage compared with healthy subjects. The present study evaluated the effects of adenovirus-mediated transduction of Dickkopf-1 (Dkk1), a Wnt/β-
catenin signaling inhibitor, on the development of pulmonary
silicosis in mice. Consistent with previous human clinical studies, our experimental studies in mice demonstrated an aberrant Wnt/β-
catenin signaling activity coinciding with increased Wnt3a and Dkk1
proteins and
inflammation in lungs of
silica-induced
silicosis mice compared with controls. Intratracheal delivery of adenovirus expressing murine Dkk1 (AdDkk1) inhibited Wnt/β-
catenin activity in mouse lungs. The adenovirus-mediated Dkk1 gene transduction demonstrated the potential to prevent
silicosis development and ameliorate
silica-induced lung fibrogenesis in mice, accompanied by the reduced expression of epithelia--mesenchymal transition markers and deposition of
extracellular matrix proteins compared with mice treated with "null" adenoviral vector. Mechanistically, AdDkk1 is able to attenuate the lung
silicosis by inhibiting a
silica-induced spike in TGF-β/Smad signaling. In addition, the forced expression of Dkk1 suppressed
silica-induced epithelial cell proliferation in polarized human bronchial epithelial cells. This study provides insight into the underlying role of Wnt/β-
catenin signaling in promoting the pathogenesis of
silicosis and is proof-of-concept that targeting Wnt/β-
catenin signaling by Dkk1 gene transduction may be an alternative approach in the prevention and treatment of
silicosis lung disease.