TY - JOUR T1 - Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models JF - bioRxiv DO - 10.1101/2021.03.30.437658 SP - 2021.03.30.437658 AU - Juliana Bragazzi Cunha AU - Jared S Elenbaas AU - Dhiman Maitra AU - Ning Kuo AU - Rodrigo Azuero-Dajud AU - Allison C Ferguson AU - Megan S Griffin AU - Stephen I Lentz AU - Jordan A Shavit AU - M Bishr Omary Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/03/30/2021.03.30.437658.abstract N2 - 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.Competing Interest StatementThe authors have declared no competing interest. ER -