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...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-05-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-88668-9 |
| _version_ | 1818754121377775616 |
|---|---|
| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-18T05:18:13Z |
| format | Article |
| id | doaj.art-e06a443978e94eb7b7e1577a00409af2 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-18T05:18:13Z |
| publishDate | 2021-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-e06a443978e94eb7b7e1577a00409af22022-12-21T21:19:44ZengNature PortfolioScientific Reports2045-23222021-05-0111111010.1038/s41598-021-88668-9Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria modelsJuliana Bragazzi Cunha0Jared S. Elenbaas1Dhiman Maitra2Ning Kuo3Rodrigo Azuero-Dajud4Allison C. Ferguson5Megan S. Griffin6Stephen I. Lentz7Jordan A. Shavit8M. Bishr Omary9Center for Advanced Biotechnology and Medicine, Rutgers UniversityMedical Scientist Training Program, Washington UniversityCenter for Advanced Biotechnology and Medicine, Rutgers UniversityCenter for Advanced Biotechnology and Medicine, Rutgers UniversityCenter for Advanced Biotechnology and Medicine, Rutgers UniversityDepartment of Pediatrics, Division of Pediatric Hematology/Oncology, University of MichiganDepartment of Pediatrics, Division of Pediatric Hematology/Oncology, University of MichiganDepartment of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of MichiganDepartment of Pediatrics, Division of Pediatric Hematology/Oncology, University of MichiganCenter for Advanced Biotechnology and Medicine, Rutgers UniversityAbstract 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.https://doi.org/10.1038/s41598-021-88668-9 |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models |
| title_sort | acitretin mitigates uroporphyrin induced bone defects in congenital erythropoietic porphyria models |
| url | https://doi.org/10.1038/s41598-021-88668-9 |
| work_keys_str_mv | AT julianabragazzicunha acitretinmitigatesuroporphyrininducedbonedefectsincongenitalerythropoieticporphyriamodels AT jaredselenbaas acitretinmitigatesuroporphyrininducedbonedefectsincongenitalerythropoieticporphyriamodels AT dhimanmaitra acitretinmitigatesuroporphyrininducedbonedefectsincongenitalerythropoieticporphyriamodels AT ningkuo acitretinmitigatesuroporphyrininducedbonedefectsincongenitalerythropoieticporphyriamodels AT rodrigoazuerodajud acitretinmitigatesuroporphyrininducedbonedefectsincongenitalerythropoieticporphyriamodels AT allisoncferguson acitretinmitigatesuroporphyrininducedbonedefectsincongenitalerythropoieticporphyriamodels AT megansgriffin acitretinmitigatesuroporphyrininducedbonedefectsincongenitalerythropoieticporphyriamodels AT stephenilentz acitretinmitigatesuroporphyrininducedbonedefectsincongenitalerythropoieticporphyriamodels AT jordanashavit acitretinmitigatesuroporphyrininducedbonedefectsincongenitalerythropoieticporphyriamodels AT mbishromary acitretinmitigatesuroporphyrininducedbonedefectsincongenitalerythropoieticporphyriamodels |