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Hedgehog pathway inhibitors significantly reduce the formation of heterotopic ossification in a direct trauma/burn mouse model

Atanu Chakraborty, Jelena Gvozdenovic-Jeremic, Fang Wang, Stephen W. Hoag, Ekaterina Vert-Wong, View ORCID ProfileRyan M. Pearson
doi: https://doi.org/10.1101/2021.01.31.429058
Atanu Chakraborty
1Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy. 20 N. Pine Street, Baltimore and MD 21201
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Jelena Gvozdenovic-Jeremic
4Nostopharma LLC. 10319 Westlake Dr. #241, Bethesda, MD, 20817.
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  • For correspondence: jelenaj@nostopharma.com
Fang Wang
1Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy. 20 N. Pine Street, Baltimore and MD 21201
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Stephen W. Hoag
1Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy. 20 N. Pine Street, Baltimore and MD 21201
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Ekaterina Vert-Wong
4Nostopharma LLC. 10319 Westlake Dr. #241, Bethesda, MD, 20817.
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  • For correspondence: jelenaj@nostopharma.com
Ryan M. Pearson
1Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy. 20 N. Pine Street, Baltimore and MD 21201
2Department of Microbiology and Immunology, University of Maryland School of Medicine. 655 W. Baltimore Street, Baltimore, MD 21201
3Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine. 22 S. Greene Street, Baltimore, MD 21201
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  • For correspondence: rpearson@rx.umaryland.edu
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Abstract

Heterotopic ossification (HO), either acquired or hereditary, is featured by ectopic bone formation outside of the normal skeleton. The acquired form of HO is a debilitating and common complication of musculoskeletal trauma, central nervous system injury, burns, combat trauma, hip and elbow fractures, and total joint replacement surgeries. It can be characterized as abnormal bone formation that occurs mostly by endochondral ossification. Recent studies have implicated inflammation and dysregulation of Hedgehog (Hh) signaling as major early contributors to HO formation. Here, we demonstrate that administration of the Hh pathway inhibitor, arsenic trioxide (ATO), prevented acquired HO in a clinically-relevant trauma/burn mouse model. We further evaluated the effects of two additional Hh pathway antagonists: cholecalciferol and pravastatin on mitigating osteoblast differentiation. Finally, we assessed the effect of a combination of Hh pathway inhibitors on reducing systemic proinflammatory responses. A targeted combination approach using Hh pathway inhibitors may offer potential therapeutic benefits though targeting differential components of the Hh pathway. Taken together, our study demonstrates that the administration of single or multiple Hh pathway inhibitors may have the potential to reduce the formation of acquired HO.

Competing Interest Statement

JGJ and EVW are co-founders of Nostopharma LLC. All other authors declare no conflicts of interest with this work.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 01, 2021.
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Hedgehog pathway inhibitors significantly reduce the formation of heterotopic ossification in a direct trauma/burn mouse model
Atanu Chakraborty, Jelena Gvozdenovic-Jeremic, Fang Wang, Stephen W. Hoag, Ekaterina Vert-Wong, Ryan M. Pearson
bioRxiv 2021.01.31.429058; doi: https://doi.org/10.1101/2021.01.31.429058
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Hedgehog pathway inhibitors significantly reduce the formation of heterotopic ossification in a direct trauma/burn mouse model
Atanu Chakraborty, Jelena Gvozdenovic-Jeremic, Fang Wang, Stephen W. Hoag, Ekaterina Vert-Wong, Ryan M. Pearson
bioRxiv 2021.01.31.429058; doi: https://doi.org/10.1101/2021.01.31.429058

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