title: Bone morphogenetic protein-inducer tilorone identified by high-throughput screening is antifibrotic in vivo.
abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a poor prognosis and very few therapeutic options. On the molecular level, patients with IPF have increased amounts of the bone morphogenetic protein (BMP) inhibitor gremlin in their lungs, which results in decreased BMP signaling, and an increase in transforming growth factor-β signaling. Based on these findings, we hypothesized that restoration of the impaired BMP signaling would offer a novel strategy for the prevention of fibrosis progression or for the treatment of pulmonary fibrosis. We used reporter cell lines and high-throughput screening of a chemical compound library as an approach to finding molecules that increase BMP signaling in lung epithelial cells, without increasing transforming growth factor-β signaling. The most promising candidate drug was analyzed further by studying its effects on BMP target gene expression, Smad protein phosphorylation, and a mouse model of silica-induced pulmonary fibrosis. The most promising drug candidate, tilorone, induced BMP signaling in the reporter cells and increased the expression of BMP-7 and a BMP target gene, Id3, in lung epithelial A549 cells. In a mouse model of pulmonary fibrosis, tilorone decreased lung hydroxyproline content and the expression of collagen genes Col1A1 and Col3A1. Mice treated with tilorone showed markedly decreased histological changes, compared with untreated mice. These findings indicate that tilorone has biologically significant antifibrotic properties.
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Leppäranta
authors.forename: Jussi M
authors.initials: JM
authors.lastname: Tikkanen
authors.forename: Maxim M
authors.initials: MM
authors.lastname: Bespalov
authors.forename: Katri
authors.initials: K
authors.lastname: Koli
authors.forename: Marjukka
authors.initials: M
authors.lastname: Myllärniemi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D055419:Bone Morphogenetic Protein 7 / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000096:biosynthesis; D000090602:Collagen Type I, alpha 1 Chain; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013994:Tilorone / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; C525820:bmp7 protein, mouse; C067679:Idb3 protein, mouse; C075640:ID3 protein, human; D013994:Tilorone