Tenomodulin knockout mice exhibit worse late healing outcomes with augmented trauma-induced heterotopic ossification of Achilles tendon

Abstract Heterotopic ossification (HO) represents a common problem after tendon injury with no effective treatment yet being developed. Tenomodulin (Tnmd), the best-known mature marker for tendon lineage cells, has important effects in tendon tissue aging and function. We have reported that loss of...

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Autores principales:	Manuel Delgado Caceres, Katharina Angerpointner, Michael Galler, Dasheng Lin, Philipp A. Michel, Christoph Brochhausen, Xin Lu, Adithi R. Varadarajan, Jens Warfsmann, Richard Stange, Volker Alt, Christian G. Pfeifer, Denitsa Docheva
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Cytology QH573-671
Acceso en línea:	https://doaj.org/article/9c34c922da0345759afc57f0147bba83
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spelling	oai:doaj.org-article:9c34c922da0345759afc57f0147bba832021-11-07T12:04:50ZTenomodulin knockout mice exhibit worse late healing outcomes with augmented trauma-induced heterotopic ossification of Achilles tendon10.1038/s41419-021-04298-z2041-4889https://doaj.org/article/9c34c922da0345759afc57f0147bba832021-11-01T00:00:00Zhttps://doi.org/10.1038/s41419-021-04298-zhttps://doaj.org/toc/2041-4889Abstract Heterotopic ossification (HO) represents a common problem after tendon injury with no effective treatment yet being developed. Tenomodulin (Tnmd), the best-known mature marker for tendon lineage cells, has important effects in tendon tissue aging and function. We have reported that loss of Tnmd leads to inferior early tendon repair characterized by fibrovascular scaring and therefore hypothesized that its lack will persistently cause deficient repair during later stages. Tnmd knockout (Tnmd −/− ) and wild-type (WT) animals were subjected to complete Achilles tendon surgical transection followed by end-to-end suture. Lineage tracing revealed a reduction in tendon-lineage cells marked by ScleraxisGFP, but an increase in alpha smooth muscle actin myofibroblasts in Tnmd − /− tendon scars. At the proliferative stage, more pro-inflammatory M1 macrophages and larger collagen II cartilaginous template were detected in this group. At the remodeling stage, histological scoring revealed lower repair quality in the injured Tnmd −/− tendons, which was coupled with higher HO quantified by micro-CT. Tendon biomechanical properties were compromised in both groups upon injury, however we identified an abnormal stiffening of non-injured Tnmd −/ − tendons, which possessed higher static and dynamic E-moduli. Pathologically thicker and abnormally shaped collagen fibrils were observed by TEM in Tnmd −/− tendons and this, together with augmented HO, resulted in diminished running capacity of Tnmd −/− mice. These novel findings demonstrate that Tnmd plays a protecting role against trauma-induced endochondral HO and can inspire the generation of novel therapeutics to accelerate repair.Manuel Delgado CaceresKatharina AngerpointnerMichael GallerDasheng LinPhilipp A. MichelChristoph BrochhausenXin LuAdithi R. VaradarajanJens WarfsmannRichard StangeVolker AltChristian G. PfeiferDenitsa DochevaNature Publishing GrouparticleCytologyQH573-671ENCell Death and Disease, Vol 12, Iss 11, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cytology QH573-671
spellingShingle	Cytology QH573-671 Manuel Delgado Caceres Katharina Angerpointner Michael Galler Dasheng Lin Philipp A. Michel Christoph Brochhausen Xin Lu Adithi R. Varadarajan Jens Warfsmann Richard Stange Volker Alt Christian G. Pfeifer Denitsa Docheva Tenomodulin knockout mice exhibit worse late healing outcomes with augmented trauma-induced heterotopic ossification of Achilles tendon
description	Abstract Heterotopic ossification (HO) represents a common problem after tendon injury with no effective treatment yet being developed. Tenomodulin (Tnmd), the best-known mature marker for tendon lineage cells, has important effects in tendon tissue aging and function. We have reported that loss of Tnmd leads to inferior early tendon repair characterized by fibrovascular scaring and therefore hypothesized that its lack will persistently cause deficient repair during later stages. Tnmd knockout (Tnmd −/− ) and wild-type (WT) animals were subjected to complete Achilles tendon surgical transection followed by end-to-end suture. Lineage tracing revealed a reduction in tendon-lineage cells marked by ScleraxisGFP, but an increase in alpha smooth muscle actin myofibroblasts in Tnmd − /− tendon scars. At the proliferative stage, more pro-inflammatory M1 macrophages and larger collagen II cartilaginous template were detected in this group. At the remodeling stage, histological scoring revealed lower repair quality in the injured Tnmd −/− tendons, which was coupled with higher HO quantified by micro-CT. Tendon biomechanical properties were compromised in both groups upon injury, however we identified an abnormal stiffening of non-injured Tnmd −/ − tendons, which possessed higher static and dynamic E-moduli. Pathologically thicker and abnormally shaped collagen fibrils were observed by TEM in Tnmd −/− tendons and this, together with augmented HO, resulted in diminished running capacity of Tnmd −/− mice. These novel findings demonstrate that Tnmd plays a protecting role against trauma-induced endochondral HO and can inspire the generation of novel therapeutics to accelerate repair.
format	article
author	Manuel Delgado Caceres Katharina Angerpointner Michael Galler Dasheng Lin Philipp A. Michel Christoph Brochhausen Xin Lu Adithi R. Varadarajan Jens Warfsmann Richard Stange Volker Alt Christian G. Pfeifer Denitsa Docheva
author_facet	Manuel Delgado Caceres Katharina Angerpointner Michael Galler Dasheng Lin Philipp A. Michel Christoph Brochhausen Xin Lu Adithi R. Varadarajan Jens Warfsmann Richard Stange Volker Alt Christian G. Pfeifer Denitsa Docheva
author_sort	Manuel Delgado Caceres
title	Tenomodulin knockout mice exhibit worse late healing outcomes with augmented trauma-induced heterotopic ossification of Achilles tendon
title_short	Tenomodulin knockout mice exhibit worse late healing outcomes with augmented trauma-induced heterotopic ossification of Achilles tendon
title_full	Tenomodulin knockout mice exhibit worse late healing outcomes with augmented trauma-induced heterotopic ossification of Achilles tendon
title_fullStr	Tenomodulin knockout mice exhibit worse late healing outcomes with augmented trauma-induced heterotopic ossification of Achilles tendon
title_full_unstemmed	Tenomodulin knockout mice exhibit worse late healing outcomes with augmented trauma-induced heterotopic ossification of Achilles tendon
title_sort	tenomodulin knockout mice exhibit worse late healing outcomes with augmented trauma-induced heterotopic ossification of achilles tendon
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/9c34c922da0345759afc57f0147bba83
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Tenomodulin knockout mice exhibit worse late healing outcomes with augmented trauma-induced heterotopic ossification of Achilles tendon

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