Clinically applicable antianginal agents suppress osteoblastic transformation of myogenic cells and heterotopic ossifications in mice

J Bone Miner Metab. 2013 Jan;31(1):26-33. doi: 10.1007/s00774-012-0380-2. Epub 2012 Aug 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / genetics
  • Activin Receptors, Type I / metabolism
  • Animals
  • Bone Morphogenetic Protein 2 / genetics
  • Bone Morphogenetic Protein 2 / metabolism
  • Calcium Channel Blockers / pharmacology*
  • Cell Line
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Fendiline / pharmacology*
  • Inhibitor of Differentiation Protein 1 / biosynthesis
  • Inhibitor of Differentiation Protein 1 / genetics
  • Mice
  • Mice, Mutant Strains
  • Muscle Cells / metabolism*
  • Muscle Cells / pathology
  • Mutation
  • Myositis Ossificans / drug therapy*
  • Myositis Ossificans / genetics
  • Myositis Ossificans / metabolism
  • Myositis Ossificans / pathology
  • Ossification, Heterotopic / drug therapy*
  • Ossification, Heterotopic / metabolism
  • Ossification, Heterotopic / pathology
  • Osteoblasts / metabolism*
  • Osteoblasts / pathology
  • Perhexiline / analogs & derivatives*
  • Perhexiline / pharmacology
  • Promoter Regions, Genetic / genetics
  • Smad Proteins / genetics
  • Smad Proteins / metabolism


  • Bmp2 protein, mouse
  • Bone Morphogenetic Protein 2
  • Calcium Channel Blockers
  • Idb1 protein, mouse
  • Inhibitor of Differentiation Protein 1
  • Smad Proteins
  • Activin Receptors, Type I
  • Acvr1 protein, mouse
  • perhexiline maleate
  • Perhexiline
  • Fendiline