SAG therapy restores bone growth and reduces enchondroma incidence in a model of skeletal chondrodysplasias caused by Ihh deficiency

Inactivation mutations in the Indian hedgehog (Ihh) gene in humans cause numerous skeletal chondrodysplasias, including acrocapitofemoral dysplasia, brachydactyly type A1, and human short stature. The lack of an appropriate human-relevant model to accurately represent these chondrodysplasias has ham...

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Autores principales:	Xinhua Li, Shuting Yang, Zahra Chinipardaz, Eiki Koyama, Shuying Yang
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Indian hedgehog acrocapitofemoral dysplasia brachydactyly type A1 enchondroma primary cilia Genetics QH426-470 Cytology QH573-671
Acceso en línea:	https://doaj.org/article/91e93e5844814980b3ca6a198b49e200
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spelling	oai:doaj.org-article:91e93e5844814980b3ca6a198b49e2002021-11-10T04:27:52ZSAG therapy restores bone growth and reduces enchondroma incidence in a model of skeletal chondrodysplasias caused by Ihh deficiency2329-050110.1016/j.omtm.2021.09.015https://doaj.org/article/91e93e5844814980b3ca6a198b49e2002021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2329050121001534https://doaj.org/toc/2329-0501Inactivation mutations in the Indian hedgehog (Ihh) gene in humans cause numerous skeletal chondrodysplasias, including acrocapitofemoral dysplasia, brachydactyly type A1, and human short stature. The lack of an appropriate human-relevant model to accurately represent these chondrodysplasias has hampered the identification of clinically effective treatments. Here, we established a mouse model of human skeletal dysplasia induced by Ihh gene mutations via ablation of Ihh in Aggrecan-positive (Acan+) cells using Aggrecan (Acan)-creERT transgenic mice. Smoothen agonist (SAG) promoted Hh activity and rescued chondrocyte proliferation and differentiation by stimulating smoothened trafficking to the cilium in Ihh-silenced cells. SAG treatment corrected mouse stature and significantly decreased mortality without evidence of toxicity. Moreover, Ihh ablation in Acan+ cells produced enchondroma-like tissues near the growth plates that were significantly reduced by SAG treatment. These results demonstrated that SAG effectively treats skeletal dysplasia caused by Ihh gene mutations in a mouse model, suggesting that SAG may represent a potential drug for the treatment of these diseases and/or enchondromas.Xinhua LiShuting YangZahra ChinipardazEiki KoyamaShuying YangElsevierarticleIndian hedgehogacrocapitofemoral dysplasiabrachydactyly type A1enchondromaprimary ciliaGeneticsQH426-470CytologyQH573-671ENMolecular Therapy: Methods & Clinical Development, Vol 23, Iss , Pp 461-475 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Indian hedgehog acrocapitofemoral dysplasia brachydactyly type A1 enchondroma primary cilia Genetics QH426-470 Cytology QH573-671
spellingShingle	Indian hedgehog acrocapitofemoral dysplasia brachydactyly type A1 enchondroma primary cilia Genetics QH426-470 Cytology QH573-671 Xinhua Li Shuting Yang Zahra Chinipardaz Eiki Koyama Shuying Yang SAG therapy restores bone growth and reduces enchondroma incidence in a model of skeletal chondrodysplasias caused by Ihh deficiency
description	Inactivation mutations in the Indian hedgehog (Ihh) gene in humans cause numerous skeletal chondrodysplasias, including acrocapitofemoral dysplasia, brachydactyly type A1, and human short stature. The lack of an appropriate human-relevant model to accurately represent these chondrodysplasias has hampered the identification of clinically effective treatments. Here, we established a mouse model of human skeletal dysplasia induced by Ihh gene mutations via ablation of Ihh in Aggrecan-positive (Acan+) cells using Aggrecan (Acan)-creERT transgenic mice. Smoothen agonist (SAG) promoted Hh activity and rescued chondrocyte proliferation and differentiation by stimulating smoothened trafficking to the cilium in Ihh-silenced cells. SAG treatment corrected mouse stature and significantly decreased mortality without evidence of toxicity. Moreover, Ihh ablation in Acan+ cells produced enchondroma-like tissues near the growth plates that were significantly reduced by SAG treatment. These results demonstrated that SAG effectively treats skeletal dysplasia caused by Ihh gene mutations in a mouse model, suggesting that SAG may represent a potential drug for the treatment of these diseases and/or enchondromas.
format	article
author	Xinhua Li Shuting Yang Zahra Chinipardaz Eiki Koyama Shuying Yang
author_facet	Xinhua Li Shuting Yang Zahra Chinipardaz Eiki Koyama Shuying Yang
author_sort	Xinhua Li
title	SAG therapy restores bone growth and reduces enchondroma incidence in a model of skeletal chondrodysplasias caused by Ihh deficiency
title_short	SAG therapy restores bone growth and reduces enchondroma incidence in a model of skeletal chondrodysplasias caused by Ihh deficiency
title_full	SAG therapy restores bone growth and reduces enchondroma incidence in a model of skeletal chondrodysplasias caused by Ihh deficiency
title_fullStr	SAG therapy restores bone growth and reduces enchondroma incidence in a model of skeletal chondrodysplasias caused by Ihh deficiency
title_full_unstemmed	SAG therapy restores bone growth and reduces enchondroma incidence in a model of skeletal chondrodysplasias caused by Ihh deficiency
title_sort	sag therapy restores bone growth and reduces enchondroma incidence in a model of skeletal chondrodysplasias caused by ihh deficiency
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/91e93e5844814980b3ca6a198b49e200
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SAG therapy restores bone growth and reduces enchondroma incidence in a model of skeletal chondrodysplasias caused by Ihh deficiency

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