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Echinomycin in the prevention of heterotopic ossification - An experimental antibiotic agent shows promising results in a murine model


Zimmermann, S M; Würgler-Hauri, C C; Wanner, G A; Simmen, H P; Werner, C M L (2013). Echinomycin in the prevention of heterotopic ossification - An experimental antibiotic agent shows promising results in a murine model. Injury, 44(4):570-575.

Abstract

BACKGROUND: Heterotopic ossification (HO) frequently causes complications following orthopaedic and trauma surgery and may drastically reduce the postoperative outcome due to pain and joint contracture. Current therapeutic options include NSAID's and local radiation. However, both options of prevention show disadvantages such as delayed fracture healing and impaired ossification as well as other side effects.(9) Our goal was to investigate a novel approach in the prevention of heterotopic ossification by pharmacologically interfering with the molecular signalling pathways involved in this process. Hypoxia leads to numerous effects on a cellular level, one of which is the activation of the transcriptional complex hypoxia-inducible factor (HIF).(19) Among several other actions, the HIF1-α signalling pathway in turn regulates angiogenesis through induction of the expression of vascular endothelial growth factor (VEGF).(21) We hypothesised that by pharmacologically interfering with the HIF-1α signalling pathway, the amount of HO formation may be reduced. Echinomycin is a known inhibitor of HIF-1-alpha and was used in our study with the aim to prevent HO from forming. METHODS: We examined the effect of Echinomycin on HO formation in a murine model where an Achilles tenotomy was performed. This has previously been shown to reliably produce islets of heterotopic ossification within the soft tissue of mouse hind limbs at 10 weeks after surgery. The control group underwent Achilles tenotomy only, whereas the Echinomycin group additionally received Echinomycin subcutaneously. After trial completion, the limbs were harvested and Micro-CT was performed. Heterotopic bone volume was then identified in 3d images and quantified. RESULTS: We found a highly significant reduction in the bone volume following subcutaneous administration of Echinomycin compared to the control group. CONCLUSION: Although a substantial reduction could be achieved, it was not possible to completely prevent heterotopic ossification from forming. Further studies have yet to be conducted to optimise the results by altering the dosage and duration of administration as well as investigate the mechanism by which Echinomycin led to the reduction of HO formation.

Abstract

BACKGROUND: Heterotopic ossification (HO) frequently causes complications following orthopaedic and trauma surgery and may drastically reduce the postoperative outcome due to pain and joint contracture. Current therapeutic options include NSAID's and local radiation. However, both options of prevention show disadvantages such as delayed fracture healing and impaired ossification as well as other side effects.(9) Our goal was to investigate a novel approach in the prevention of heterotopic ossification by pharmacologically interfering with the molecular signalling pathways involved in this process. Hypoxia leads to numerous effects on a cellular level, one of which is the activation of the transcriptional complex hypoxia-inducible factor (HIF).(19) Among several other actions, the HIF1-α signalling pathway in turn regulates angiogenesis through induction of the expression of vascular endothelial growth factor (VEGF).(21) We hypothesised that by pharmacologically interfering with the HIF-1α signalling pathway, the amount of HO formation may be reduced. Echinomycin is a known inhibitor of HIF-1-alpha and was used in our study with the aim to prevent HO from forming. METHODS: We examined the effect of Echinomycin on HO formation in a murine model where an Achilles tenotomy was performed. This has previously been shown to reliably produce islets of heterotopic ossification within the soft tissue of mouse hind limbs at 10 weeks after surgery. The control group underwent Achilles tenotomy only, whereas the Echinomycin group additionally received Echinomycin subcutaneously. After trial completion, the limbs were harvested and Micro-CT was performed. Heterotopic bone volume was then identified in 3d images and quantified. RESULTS: We found a highly significant reduction in the bone volume following subcutaneous administration of Echinomycin compared to the control group. CONCLUSION: Although a substantial reduction could be achieved, it was not possible to completely prevent heterotopic ossification from forming. Further studies have yet to be conducted to optimise the results by altering the dosage and duration of administration as well as investigate the mechanism by which Echinomycin led to the reduction of HO formation.

Citations

9 citations in Web of Science®
15 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Trauma Surgery
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2013
Deposited On:21 Feb 2013 13:56
Last Modified:05 Apr 2016 16:34
Publisher:Elsevier
ISSN:0020-1383
Publisher DOI:https://doi.org/10.1016/j.injury.2012.12.030
PubMed ID:23398900

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