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The pseudoxanthoma elasticum zebrafish model contributes to novel pathophysiological insights and therapeutic strategies in ectopic mineralization

Lisa Dangreau (UGent) , Lukas Nollet (UGent) , Matthias Van Gils, Andy Willaert (UGent) , Paul Coucke (UGent) and Olivier Vanakker (UGent)
(2023) Belgian Society for Human Genetics (BeSHG) Annual Meeting 2023 : To DNA and beyond, Abstracts.
Author
Organization
Abstract
Pseudoxanthoma elasticum (PXE) is an autosomal recessive hallmark disorder of ectopic calcification (EC), where EC and fragmentation of elastic fibers result in skin, ocular and cardiovascular symptoms. PXE is most commonly caused by bi-alllelic pathogenic variants in the ABCC6 gene, encoding an ATP-dependent transmembrane transporter of which the substrate is unknown. With an incompletely understood pathophysiology and being an intractable disease, PXE exemplifies how disease-modeling in zebrafish can help to better understand an EC disorder and provide novel strategies for treatment. The ABCC6 gene has two orthologs in zebrafish, abcc6a and abcc6b. We developed a complete abcc6a knockout zebrafish model using CRISPR/Cas9, showing that it has an essential role in controlling mineralization. The model developed hypermineralization of notochord and ribs starting embryonically and progressing in adulthood with development of scoliosis. This indicated a direct relation between loss of abcc6a expression and dysregulated osteogenesis. We went on to show that an excessive DNA Damage Response was present in the abcc6a-/- fish using expression analysis of DDR/PARP1 targets with QRT-PCR. PARP1 and the ATM‒p21‒p53 axis were found to be significantly increased. In addition, PARP1 downstream targets IL-6, signal transducer and activator of transcription 1/3, TET1, and RUNX2 were upregulated. Finally, we validated our PXE zebrafish as a model for compound screening in EC by showing a reduction of the hypermineralization with known effective drugs such as vitamin K1, etidronate and magnesium citrate. Based on this validation study we demonstrated for the first time that sodium thiosulphate and PARP-inhibition using minocycline are able to attenuate the PXE-related mineralization in vivo. Overall, we demonstrate how to use the PXE zebrafish model in translational research from mechanistic insights to in vivo compound screening.

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MLA
Dangreau, Lisa, et al. “The Pseudoxanthoma Elasticum Zebrafish Model Contributes to Novel Pathophysiological Insights and Therapeutic Strategies in Ectopic Mineralization.” Belgian Society for Human Genetics (BeSHG) Annual Meeting 2023 : To DNA and beyond, Abstracts, 2023.
APA
Dangreau, L., Nollet, L., Van Gils, M., Willaert, A., Coucke, P., & Vanakker, O. (2023). The pseudoxanthoma elasticum zebrafish model contributes to novel pathophysiological insights and therapeutic strategies in ectopic mineralization. Belgian Society for Human Genetics (BeSHG) Annual Meeting 2023 : To DNA and beyond, Abstracts. Presented at the Belgian Society for Human Genetics (BeSHG) Annual Meeting 2023 : To DNA and beyond, Charleroi, Belgium.
Chicago author-date
Dangreau, Lisa, Lukas Nollet, Matthias Van Gils, Andy Willaert, Paul Coucke, and Olivier Vanakker. 2023. “The Pseudoxanthoma Elasticum Zebrafish Model Contributes to Novel Pathophysiological Insights and Therapeutic Strategies in Ectopic Mineralization.” In Belgian Society for Human Genetics (BeSHG) Annual Meeting 2023 : To DNA and beyond, Abstracts.
Chicago author-date (all authors)
Dangreau, Lisa, Lukas Nollet, Matthias Van Gils, Andy Willaert, Paul Coucke, and Olivier Vanakker. 2023. “The Pseudoxanthoma Elasticum Zebrafish Model Contributes to Novel Pathophysiological Insights and Therapeutic Strategies in Ectopic Mineralization.” In Belgian Society for Human Genetics (BeSHG) Annual Meeting 2023 : To DNA and beyond, Abstracts.
Vancouver
1.
Dangreau L, Nollet L, Van Gils M, Willaert A, Coucke P, Vanakker O. The pseudoxanthoma elasticum zebrafish model contributes to novel pathophysiological insights and therapeutic strategies in ectopic mineralization. In: Belgian Society for Human Genetics (BeSHG) Annual Meeting 2023 : To DNA and beyond, Abstracts. 2023.
IEEE
[1]
L. Dangreau, L. Nollet, M. Van Gils, A. Willaert, P. Coucke, and O. Vanakker, “The pseudoxanthoma elasticum zebrafish model contributes to novel pathophysiological insights and therapeutic strategies in ectopic mineralization,” in Belgian Society for Human Genetics (BeSHG) Annual Meeting 2023 : To DNA and beyond, Abstracts, Charleroi, Belgium, 2023.
@inproceedings{01H2T1933HKH0CV3RP8AYSAJJG,
  abstract     = {{Pseudoxanthoma elasticum (PXE) is an autosomal recessive hallmark disorder of ectopic calcification (EC), where EC and fragmentation of elastic fibers result in skin, ocular and cardiovascular symptoms. PXE is most commonly caused by bi-alllelic pathogenic variants in the ABCC6 gene, encoding an ATP-dependent transmembrane transporter of which the substrate is unknown. With an incompletely understood pathophysiology and being an intractable disease, PXE exemplifies how disease-modeling in zebrafish can help to better understand an EC disorder and provide novel strategies for treatment. The ABCC6 gene has two orthologs in zebrafish, abcc6a and abcc6b. We developed a complete abcc6a knockout zebrafish model using CRISPR/Cas9, showing that it has an essential role in controlling mineralization. The model developed hypermineralization of notochord and ribs starting embryonically and progressing in adulthood with development of scoliosis. This indicated a direct relation between loss of abcc6a expression and dysregulated osteogenesis. We went on to show that an excessive DNA Damage Response was present in the abcc6a-/- fish using expression analysis of DDR/PARP1 targets with QRT-PCR. PARP1 and the ATM‒p21‒p53 axis were found to be significantly increased. In addition, PARP1 downstream targets IL-6, signal transducer and activator of transcription 1/3, TET1, and RUNX2 were upregulated. Finally, we validated our PXE zebrafish as a model for compound screening in EC by showing a reduction of the hypermineralization with known effective drugs such as vitamin K1, etidronate and magnesium citrate. Based on this validation study we demonstrated for the first time that sodium thiosulphate and PARP-inhibition using minocycline are able to attenuate the PXE-related mineralization in vivo. Overall, we demonstrate how to use the PXE zebrafish model in translational research from mechanistic insights to in vivo compound screening.}},
  author       = {{Dangreau, Lisa and Nollet, Lukas and Van Gils, Matthias and Willaert, Andy and Coucke, Paul and Vanakker, Olivier}},
  booktitle    = {{Belgian Society for Human Genetics (BeSHG) Annual Meeting 2023 : To DNA and beyond, Abstracts}},
  language     = {{eng}},
  location     = {{Charleroi, Belgium}},
  title        = {{The pseudoxanthoma elasticum zebrafish model contributes to novel pathophysiological insights and therapeutic strategies in ectopic mineralization}},
  year         = {{2023}},
}