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Desloratadine inhibits heterotopic ossification by suppression of BMP2-Smad1/5/8 signaling.

Authors
  • Kusano, Taiki1, 2, 3
  • Nakatani, Masashi2
  • Ishiguro, Naoki1
  • Ohno, Kinji3
  • Yamamoto, Naoki4
  • Morita, Mitsuhiro5
  • Yamada, Harumoto5
  • Uezumi, Akiyoshi6
  • Tsuchida, Kunihiro2
  • 1 Department of Orthopaedic Surgery, Graduate School of Medicine, Nagoya University, Nagoya, Japan. , (Japan)
  • 2 Division for Therapies against Intractable Diseases, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan. , (Japan)
  • 3 Division of Neurological Diseases and Cancer, Graduate School of Medicine, Nagoya University, Nagoya, Japan. , (Japan)
  • 4 Center for Joint Research Facilities Support, Fujita Health University, Research Promotion and Support Headquarters, Toyoake, Japan. , (Japan)
  • 5 Department of Orthopaedic Surgery, Fujita Health University, Toyoake, Japan. , (Japan)
  • 6 Department of Geriatric Medicine, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, Japan. , (Japan)
Type
Published Article
Journal
Journal of Orthopaedic Research®
Publisher
Wiley (John Wiley & Sons)
Publication Date
Jun 01, 2021
Volume
39
Issue
6
Pages
1297–1304
Identifiers
DOI: 10.1002/jor.24625
PMID: 32043642
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Heterotopic ossification (HO) is a pathological condition in which ectopic bone forms within soft tissues such as skeletal muscle. Human platelet-derived growth factor receptor α positive (PDGFRα+) cells, which were proved to be the original cells of HO were incubated in osteogenic differentiation medium with Food and Drug Administration-approved compounds. Alkaline phosphatase activity was measured as a screening to inhibit osteogenic differentiation. For the compounds which inhibited osteogenic differentiation of PDGFRα+ cells, we examined dose dependency of its effect using alizarin red S staining and its cell toxicity using WST-8. In addition, regulation of bone morphogenetic proteins (BMP)-Smad signaling which is the major signal of osteogenic differentiation was investigated by Western blotting to elucidate the mechanism of osteogenesis inhibitory effect by the compound. In vivo experiment, complete transverse incision of Achilles tendons in mice was made and mice were fed the compound by mixing with drinking water after operation. Ten weeks after operation, we assessed and quantified HO by micro-computed tomography scan. Intriguingly, we discovered desloratadine inhibited osteogenic differentiation of PDGFRα+ cells using the drug repositioning method. Desloratadine inhibited osteogenic differentiation of the cells dose dependently without cell toxicity. Desloratadine suppressed phosphorylation of Smad1/5/8 induced by BMP2 in PDGFRα+ cells. In Achilles tenotomy mice model, desloratadine treatment significantly inhibited ectopic bone formation compared with control. In conclusion, we discovered desloratadine inhibited osteogenic differentiation using human PDGFRα+ cells and proved its efficacy using Achilles tenotomy ectopic bone formation model in vivo. Our study paved the way to inhibit HO in early clinical use because of its guaranteed safety. © 2020 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

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