PUBLICATION

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

Authors
Bragazzi Cunha, J., Elenbaas, J.S., Maitra, D., Kuo, N., Azuero-Dajud, R., Ferguson, A.C., Griffin, M.S., Lentz, S.I., Shavit, J.A., Omary, M.B.
ID
ZDB-PUB-210507-6
Date
2021
Source
Scientific Reports   11: 9601 (Journal)
Registered Authors
Ferguson, Allison, Shavit, Jordan
Keywords
none
MeSH Terms
  • Acitretin/pharmacology
  • Acitretin/therapeutic use*
  • Animals
  • Bone Development/drug effects*
  • Bone and Bones/drug effects*
  • Bone and Bones/metabolism
  • Cell Line
  • Disease Models, Animal
  • Porphyria, Erythropoietic/drug therapy*
  • Porphyria, Erythropoietic/genetics
  • Porphyria, Erythropoietic/metabolism
  • Uroporphyrins/genetics
  • Uroporphyrins/metabolism*
  • Zebrafish
PubMed
33953217 Full text @ Sci. Rep.
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping