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Minocycline Attenuates Excessive DNA Damage Response and Reduces Ectopic Calcification in Pseudoxanthoma Elasticum.
- Source :
-
The Journal of investigative dermatology [J Invest Dermatol] 2022 Jun; Vol. 142 (6), pp. 1629-1638.e6. Date of Electronic Publication: 2021 Nov 04. - Publication Year :
- 2022
-
Abstract
- 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 <superscript>‒/‒</superscript> 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 <superscript>‒/‒</superscript> 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.<br /> (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- ATP-Binding Cassette Transporters genetics
Animals
Core Binding Factor Alpha 1 Subunit metabolism
DNA Damage
Humans
Minocycline pharmacology
Minocycline therapeutic use
Mixed Function Oxygenases metabolism
Multidrug Resistance-Associated Proteins genetics
Proto-Oncogene Proteins metabolism
Zebrafish genetics
Zebrafish metabolism
Zebrafish Proteins genetics
MicroRNAs
Pseudoxanthoma Elasticum drug therapy
Pseudoxanthoma Elasticum genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1523-1747
- Volume :
- 142
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The Journal of investigative dermatology
- Publication Type :
- Academic Journal
- Accession number :
- 34742705
- Full Text :
- https://doi.org/10.1016/j.jid.2021.10.019