title: Clinically applicable antianginal agents suppress osteoblastic transformation of myogenic cells and heterotopic ossifications in mice.
abstract: Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by progressive heterotopic ossification. FOP is caused by a gain-of-function mutation in ACVR1 encoding the bone morphogenetic protein type II receptor, ACVR1/ALK2. The mutant receptor causes upregulation of a transcriptional factor, Id1. No therapy is available to prevent the progressive heterotopic ossification in FOP. In an effort to search for clinically applicable drugs for FOP, we screened 1,040 FDA-approved drugs for suppression of the Id1 promoter activated by the mutant ACVR1/ALK2 in C2C12 cells. We found that that two antianginal agents, fendiline hydrochloride and perhexiline maleate, suppressed the Id1 promoter in a dose-dependent manner. The drugs also suppressed the expression of native Id1 mRNA and alkaline phosphatase in a dose-dependent manner. Perhexiline but not fendiline downregulated phosphorylation of Smad 1/5/8 driven by bone morphogenetic protein (BMP)-2. We implanted crude BMPs in muscles of ddY mice and fed them fendiline or perhexiline for 30 days. Mice taking perhexiline showed a 38.0 % reduction in the volume of heterotopic ossification compared to controls, whereas mice taking fendiline showed a slight reduction of heterotopic ossification. Fendiline, perhexiline, and their possible derivatives are potentially applicable to clinical practice to prevent devastating heterotopic ossification in FOP.
authors.affiliation: Department of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Yamamoto
authors.forename: Masaki
authors.initials: M
authors.lastname: Matsushita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitoh
authors.forename: Akio
authors.initials: A
authors.lastname: Masuda
authors.forename: Mikako
authors.initials: M
authors.lastname: Ito
authors.forename: Takenobu
authors.initials: T
authors.lastname: Katagiri
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Kawai
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishiguro
authors.forename: Kinji
authors.initials: K
authors.lastname: Ohno
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005275:Fendiline / Q000494:pharmacology*; D051798:Inhibitor of Differentiation Protein 1 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D032342:Muscle Cells / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009221:Myositis Ossificans / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009999:Ossification, Heterotopic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010480:Perhexiline / Q000031:analogs & derivatives* / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D002121:Calcium Channel Blockers; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D051785:Smad Proteins; D030201:Activin Receptors, Type I; C498943:Acvr1 protein, mouse; C023470:perhexiline maleate; D010480:Perhexiline; D005275:Fendiline