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Minocycline Attenuates Excessive DNA Damage Response and Reduces Ectopic Calcification in Pseudoxanthoma Elasticum

  • Lukas Nollet
    Affiliations
    Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium

    Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

    Ectopic Mineralization Research Group Ghent, Ghent, Belgium
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  • Matthias Van Gils
    Affiliations
    Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium

    Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

    Ectopic Mineralization Research Group Ghent, Ghent, Belgium
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  • Andy Willaert
    Affiliations
    Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium

    Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
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  • Paul J. Coucke
    Affiliations
    Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium

    Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
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  • Olivier M. Vanakker
    Correspondence
    Correspondence: Olivier M. Vanakker, Center for Medical Genetics, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium.
    Affiliations
    Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium

    Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

    Ectopic Mineralization Research Group Ghent, Ghent, Belgium
    Search for articles by this author
Published:November 03, 2021DOI:https://doi.org/10.1016/j.jid.2021.10.019
      Pseudoxanthoma elasticum (PXE) is a hereditary ectopic calcification disorder affecting the skin, eyes, and blood vessels. Recently, the DNA damage response (DDR), in particular PARP1, was shown to be involved in aberrant mineralization, raising the hypothesis that excessive DDR/PARP1 signaling also contributes to PXE pathogenesis. Using dermal fibroblasts of patients with PXE and healthy controls, (lesional) skin tissue, and abcc6a‒/‒ zebrafish, we performed expression analysis of DDR/PARP1 targets with QRT-PCR, western blot, immunohistochemistry, and enzyme activity assays before and after treatment with the PARP1 inhibitor minocycline. PARP1 and the ATM‒p21‒p53 axis was found to be significantly increased in PXE. In addition, PARP1 downstream targets IL-6, signal transducer and activator of transcription 1/3, TET1, and RUNX2 were upregulated, whereas the RUNX2 antagonist microRNA-204 was decreased. In PXE fibroblasts, DDR/PARP1 signaling increased with advancing ectopic calcification. Minocycline treatment attenuated DDR/PARP1 overexpression and reduced aberrant mineralization in PXE fibroblasts and abcc6a‒/‒ zebrafish. In summary, we showed the involvement of excessive DDR/PARP1 signaling in PXE pathophysiology, identifying a signal transducer and activator of transcription‒driven cascade resulting in increased expression of the epigenetic modifier TET1 and procalcifying transcription factor RUNX2. Minocycline attenuated this deleterious molecular mechanism and reduced ectopic calcification both in vitro and in vivo, fueling the exciting prospect of a therapeutic compound for PXE.

      Abbreviation:

      ALPL (alkaline phosphatase), CI (confidence interval), CM (calcification medium), DDR (DNA damage response), miR-204 (microRNA-204), PAR (poly(adenosine diphosphate-ribose)), PPi (inorganic pyrophosphate), PXE (pseudoxanthoma elasticum), QRT-PCR (quantitative real-time reverse transcriptase‒PCR), STAT (signal transducer and activator of transcription)
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