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

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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.

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Acknowledgments

We thank Dr. Morio Kawamura at Nagoya University School of Health Science for productive discussion with us on our studies, and Ms. Keiko Itano for her technical assistance. This study was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and the Ministry of Health, Labor, and Welfare of Japan.

Conflict of interest

The authors have no conflict of interest and nothing to disclose.

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Authors and Affiliations

  1. Department of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, 466-8550, Japan

    Ryuichiro Yamamoto, Masaki Matsushita, Akio Masuda, Mikako Ito & Kinji Ohno

  2. Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Ryuichiro Yamamoto, Masaki Matsushita, Hiroshi Kitoh & Naoki Ishiguro

  3. Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan

    Takenobu Katagiri

  4. Department of Dental and Material Science, Aichi-Gakuin University School of Dentistry, Nagoya, Japan

    Tatsushi Kawai

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  1. Ryuichiro Yamamoto
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  3. Hiroshi Kitoh
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  4. Akio Masuda
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  9. Kinji Ohno
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Correspondence to Kinji Ohno.

Electronic supplementary material

Supplementary Figure 1. Real time RT-PCR of the native Id2 (A, B) and Id3 (C, D) genes in C2C12 cells in the presence of 0, 0,2, 1.0 μM fendiline hydrochloride (A, C) and perhexiline maleate (B, D). Values are normalized to the expression level of β2-microglobulin (β2MG) and also to that with 100 ng/ml of BMP-2 alone. Bars represent the mean and SE of three experiments. * P < 0.05, ** P < 0.01, *** P < 0.005, and not significant (ns) compared to BMP-2(+) but without a drug.

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Yamamoto, R., Matsushita, M., Kitoh, H. et al. Clinically applicable antianginal agents suppress osteoblastic transformation of myogenic cells and heterotopic ossifications in mice. J Bone Miner Metab 31, 26–33 (2013). https://doi.org/10.1007/s00774-012-0380-2

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  • DOI: https://doi.org/10.1007/s00774-012-0380-2

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