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

A Corrigendum to this article was published on 05 October 2012

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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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Figure 1: RAR agonists block chondrogenesis and intramuscular rBMP-2-driven heterotopic ossification.
Figure 2: Effectiveness of different retinoids against heterotopic ossification.
Figure 3: RAR-γ agonists block FOP-like heterotopic ossification.
Figure 4: Mechanisms of RAR-γ agonist action.
Figure 5: RAR-γ agonists reprogram the differentiation potentials of skeletal progenitor cells.

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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.).

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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.

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Correspondence to Maurizio Pacifici or Masahiro Iwamoto.

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The authors declare no competing financial interests.

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Shimono, K., Tung, We., Macolino, C. et al. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists. Nat Med 17, 454–460 (2011). https://doi.org/10.1038/nm.2334

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