Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models

Abstract Congenital erythropoietic porphyria (CEP) is a rare genetic disorder leading to accumulation of uro/coproporphyrin-I in tissues due to inhibition of uroporphyrinogen-III synthase. Clinical manifestations of CEP include bone fragility, severe photosensitivity and photomutilation. Currently t...

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Autores principales:	Juliana Bragazzi Cunha, Jared S. Elenbaas, Dhiman Maitra, Ning Kuo, Rodrigo Azuero-Dajud, Allison C. Ferguson, Megan S. Griffin, Stephen I. Lentz, Jordan A. Shavit, M. Bishr Omary
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e06a443978e94eb7b7e1577a00409af2
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spelling	oai:doaj.org-article:e06a443978e94eb7b7e1577a00409af22021-12-02T14:49:25ZAcitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models10.1038/s41598-021-88668-92045-2322https://doaj.org/article/e06a443978e94eb7b7e1577a00409af22021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88668-9https://doaj.org/toc/2045-2322Abstract Congenital erythropoietic porphyria (CEP) is a rare genetic disorder leading to accumulation of uro/coproporphyrin-I in tissues due to inhibition of uroporphyrinogen-III synthase. Clinical manifestations of CEP include bone fragility, severe photosensitivity and photomutilation. Currently there is no specific treatment for CEP, except bone marrow transplantation, and there is an unmet need for treating this orphan disease. Fluorescent porphyrins cause protein aggregation, which led us to hypothesize that uroporphyrin-I accumulation leads to protein aggregation and CEP-related bone phenotype. We developed a zebrafish model that phenocopies features of CEP. As in human patients, uroporphyrin-I accumulated in the bones of zebrafish, leading to impaired bone development. Furthermore, in an osteoblast-like cell line, uroporphyrin-I decreased mineralization, aggregated bone matrix proteins, activated endoplasmic reticulum stress and disrupted autophagy. Using high-throughput drug screening, we identified acitretin, a second-generation retinoid, and showed that it reduced uroporphyrin-I accumulation and its deleterious effects on bones. Our findings provide a new CEP experimental model and a potential repurposed therapeutic.Juliana Bragazzi CunhaJared S. ElenbaasDhiman MaitraNing KuoRodrigo Azuero-DajudAllison C. FergusonMegan S. GriffinStephen I. LentzJordan A. ShavitM. Bishr OmaryNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Juliana Bragazzi Cunha Jared S. Elenbaas Dhiman Maitra Ning Kuo Rodrigo Azuero-Dajud Allison C. Ferguson Megan S. Griffin Stephen I. Lentz Jordan A. Shavit M. Bishr Omary Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models
description	Abstract Congenital erythropoietic porphyria (CEP) is a rare genetic disorder leading to accumulation of uro/coproporphyrin-I in tissues due to inhibition of uroporphyrinogen-III synthase. Clinical manifestations of CEP include bone fragility, severe photosensitivity and photomutilation. Currently there is no specific treatment for CEP, except bone marrow transplantation, and there is an unmet need for treating this orphan disease. Fluorescent porphyrins cause protein aggregation, which led us to hypothesize that uroporphyrin-I accumulation leads to protein aggregation and CEP-related bone phenotype. We developed a zebrafish model that phenocopies features of CEP. As in human patients, uroporphyrin-I accumulated in the bones of zebrafish, leading to impaired bone development. Furthermore, in an osteoblast-like cell line, uroporphyrin-I decreased mineralization, aggregated bone matrix proteins, activated endoplasmic reticulum stress and disrupted autophagy. Using high-throughput drug screening, we identified acitretin, a second-generation retinoid, and showed that it reduced uroporphyrin-I accumulation and its deleterious effects on bones. Our findings provide a new CEP experimental model and a potential repurposed therapeutic.
format	article
author	Juliana Bragazzi Cunha Jared S. Elenbaas Dhiman Maitra Ning Kuo Rodrigo Azuero-Dajud Allison C. Ferguson Megan S. Griffin Stephen I. Lentz Jordan A. Shavit M. Bishr Omary
author_facet	Juliana Bragazzi Cunha Jared S. Elenbaas Dhiman Maitra Ning Kuo Rodrigo Azuero-Dajud Allison C. Ferguson Megan S. Griffin Stephen I. Lentz Jordan A. Shavit M. Bishr Omary
author_sort	Juliana Bragazzi Cunha
title	Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models
title_short	Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models
title_full	Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models
title_fullStr	Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models
title_full_unstemmed	Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models
title_sort	acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e06a443978e94eb7b7e1577a00409af2
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Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models

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