Article | Published:

Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists

Nature Medicine volume 17, pages 454460 (2011) | Download Citation

  • A Corrigendum to this article was published on 05 October 2012

This article has been updated

Abstract

Heterotopic ossification consists of ectopic bone formation within soft tissues after surgery or trauma. It can have debilitating consequences, but there is no definitive cure. Here we show that heterotopic ossification was essentially prevented in mice receiving a nuclear retinoic acid receptor-γ (RAR-γ) agonist. Side effects were minimal, and there was no significant rebound effect. To uncover the mechanisms of these responses, we treated mouse mesenchymal stem cells with an RAR-γ agonist and transplanted them into nude mice. Whereas control cells formed ectopic bone masses, cells that had been pretreated with the RAR-γ agonist did not, suggesting that they had lost their skeletogenic potential. The cells became unresponsive to rBMP-2 treatment in vitro and showed decreases in phosphorylation of Smad1, Smad5 and Smad8 and in overall levels of Smad proteins. In addition, an RAR-γ agonist blocked heterotopic ossification in transgenic mice expressing activin receptor-like kinase-2 (ALK2) Q207D, a constitutively active form of the receptor that is related to ALK2 R206H found in individuals with fibrodysplasia ossificans progressiva. The data indicate that RAR-γ agonists are potent inhibitors of heterotopic ossification in mouse models and, thus, may also be effective against injury-induced and congenital heterotopic ossification in humans.

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Change history

  • 05 October 2012

     In the version of this article initially published, the authors inadvertently used α-tubulin normalization data in the western blots shown in Figure 4b and Figure 4e from separate experiments used to generate the other bands shown. The error did not affect the main conclusions of the paper. Nonetheless, to verify the data, the authors have repeated the experiments, and the data from one such experiment are now included for both these figure panels. The authors regret the occurrence and apologize for it. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank T. Katagiri (Saitama) for the Id1-luc reporter plasmid; S. Otsuru and E. Horwitz (Children's Hospital of Philadelphia) for the GFP-expressing MSCs and culture methods; and N. Ghyselinck and P. Chambon (Institut National de la Santé et de la Recherche Médicale, Illkirch Cedex) for the RAR floxed and null mouse lines. This work was supported by contract no. W81XWH-07-1-0212 from the Department of the Army, United States Army Medical Research Acquisition Activity (M.P.) and US National Institutes of Health RO1 grant AR056837 (M.I. and M.P.).

Author information

Author notes

    • Kengo Shimono
    • , Wei-en Tung
    • , Johanna H Didizian
    • , Motomi Enomoto-Iwamoto
    • , Maurizio Pacifici
    •  & Masahiro Iwamoto

    Present address: The Children's Hospital of Philadelphia, Division of Orthopaedic Surgery, Philadelphia, Pennsylvania, USA.

Affiliations

  1. Department of Orthopaedic Surgery, Thomas Jefferson University College of Medicine, Philadelphia, Pennsylvania, USA.

    • Kengo Shimono
    • , Wei-en Tung
    • , Christine Macolino
    • , Amber Hsu-Tsai Chi
    • , Johanna H Didizian
    • , Christina Mundy
    • , Motomi Enomoto-Iwamoto
    • , Maurizio Pacifici
    •  & Masahiro Iwamoto
  2. Io Therapeutics, Irvine, California, USA.

    • Roshantha A Chandraratna
  3. School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA.

    • Yuji Mishina

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Contributions

M.I. and M.P. directed the project. K.S., W.T., C.M., A.H.-T.C., J.H.D., C.M. and M.E.-I. performed experiments, analyzed data and participated in experimental design. R.A.C. provided expertise on retinoid biology. Y.M. provided expertise in mouse genetics. M.P., K.S. and M.I. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Maurizio Pacifici or Masahiro Iwamoto.

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    Supplementary Figures 1–5 and Supplementary Methods

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DOI

https://doi.org/10.1038/nm.2334