PT  - JOURNAL ARTICLE
AU  - Atanu Chakraborty
AU  - Jelena Gvozdenovic-Jeremic
AU  - Fang Wang
AU  - Stephen W. Hoag
AU  - Ekaterina Vert-Wong
AU  - Ryan M. Pearson
TI  - Hedgehog pathway inhibitors significantly reduce the formation of heterotopic ossification in a direct trauma/burn mouse model
AID  - 10.1101/2021.01.31.429058
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.01.31.429058
4099  - http://biorxiv.org/content/early/2021/02/01/2021.01.31.429058.short
4100  - http://biorxiv.org/content/early/2021/02/01/2021.01.31.429058.full
AB  - 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 StatementJGJ and EVW are co-founders of Nostopharma LLC. All other authors declare no conflicts of interest with this work.