Potent Inhibition of Heterotopic Ossification by Nuclear Retinoic Acid Receptor γ Agonists
Heterotopic ossification (HO) consists of ectopic bone formation within soft tissues following surgery or trauma and can have debilitating consequences, but no definitive cure is available. Here we show that HO was essentially prevented in mice receiving nuclear retinoic acid receptor γ (RARγ) agoni...
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2011
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073031/ |
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pubmed-30730312011-10-03 Potent Inhibition of Heterotopic Ossification by Nuclear Retinoic Acid Receptor γ Agonists Shimono, Kengo Tung, Wei-en Macolino, Christine Chi, Amber Hsu-Tsai Didizian, Johanna J. Mundy, Christina Chandraratna, Roshantha A. Mishina, Yuji Iwamoto, Motomi Enomoto Pacifici, Maurizio Iwamoto, Masahiro Article Heterotopic ossification (HO) consists of ectopic bone formation within soft tissues following surgery or trauma and can have debilitating consequences, but no definitive cure is available. Here we show that HO was essentially prevented in mice receiving nuclear retinoic acid receptor γ (RARγ) agonists. Side effects were minimal, and there was no significant rebound effect. To uncover mechanisms, mesenchymal stem cells were treated with RARγ agonist and transplanted into nude mice. Whereas control cells formed ectopic bone masses, the RARγ agonist-pretreated cells did not, suggesting that they had lost their skeletogenic potentials. Indeed, the cells became unresponsive to rBMP-2 and exhibited reduction of Smad1/5/8 phosphorylation and overall Smad levels. As importantly, the RARγ agonists blocked HO in transgenic mice expressing constitutive-active ALK2Q207D mutant that is related to ALK2R206H found in Fibrodysplasia Ossificans Progressiva patients. The data indicate that the RARγ agonists are potent inhibitors of HO and could also be as effective against congenital HO. 2011-04-03 2011-04 /pmc/articles/PMC3073031/ /pubmed/21460849 http://dx.doi.org/10.1038/nm.2334 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
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Open Access Journal |
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Foreign Institution |
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US National Center for Biotechnology Information |
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NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Shimono, Kengo Tung, Wei-en Macolino, Christine Chi, Amber Hsu-Tsai Didizian, Johanna J. Mundy, Christina Chandraratna, Roshantha A. Mishina, Yuji Iwamoto, Motomi Enomoto Pacifici, Maurizio Iwamoto, Masahiro |
| spellingShingle |
Shimono, Kengo Tung, Wei-en Macolino, Christine Chi, Amber Hsu-Tsai Didizian, Johanna J. Mundy, Christina Chandraratna, Roshantha A. Mishina, Yuji Iwamoto, Motomi Enomoto Pacifici, Maurizio Iwamoto, Masahiro Potent Inhibition of Heterotopic Ossification by Nuclear Retinoic Acid Receptor γ Agonists |
| author_facet |
Shimono, Kengo Tung, Wei-en Macolino, Christine Chi, Amber Hsu-Tsai Didizian, Johanna J. Mundy, Christina Chandraratna, Roshantha A. Mishina, Yuji Iwamoto, Motomi Enomoto Pacifici, Maurizio Iwamoto, Masahiro |
| author_sort |
Shimono, Kengo |
| title |
Potent Inhibition of Heterotopic Ossification by Nuclear Retinoic Acid Receptor γ Agonists |
| title_short |
Potent Inhibition of Heterotopic Ossification by Nuclear Retinoic Acid Receptor γ Agonists |
| title_full |
Potent Inhibition of Heterotopic Ossification by Nuclear Retinoic Acid Receptor γ Agonists |
| title_fullStr |
Potent Inhibition of Heterotopic Ossification by Nuclear Retinoic Acid Receptor γ Agonists |
| title_full_unstemmed |
Potent Inhibition of Heterotopic Ossification by Nuclear Retinoic Acid Receptor γ Agonists |
| title_sort |
potent inhibition of heterotopic ossification by nuclear retinoic acid receptor γ agonists |
| description |
Heterotopic ossification (HO) consists of ectopic bone formation within soft tissues following surgery or trauma and can have debilitating consequences, but no definitive cure is available. Here we show that HO was essentially prevented in mice receiving nuclear retinoic acid receptor γ (RARγ) agonists. Side effects were minimal, and there was no significant rebound effect. To uncover mechanisms, mesenchymal stem cells were treated with RARγ agonist and transplanted into nude mice. Whereas control cells formed ectopic bone masses, the RARγ agonist-pretreated cells did not, suggesting that they had lost their skeletogenic potentials. Indeed, the cells became unresponsive to rBMP-2 and exhibited reduction of Smad1/5/8 phosphorylation and overall Smad levels. As importantly, the RARγ agonists blocked HO in transgenic mice expressing constitutive-active ALK2Q207D mutant that is related to ALK2R206H found in Fibrodysplasia Ossificans Progressiva patients. The data indicate that the RARγ agonists are potent inhibitors of HO and could also be as effective against congenital HO. |
| publishDate |
2011 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073031/ |
| _version_ |
1611448805740249088 |