PUBLICATION
Minocycline attenuates excessive DNA damage response and reduces ectopic calcification in pseudoxanthoma elasticum
- Authors
- Nollet, L., Van Gils, M., Willaert, A., Coucke, P.J., Vanakker, O.M.
- ID
- ZDB-PUB-211109-2
- Date
- 2021
- Source
- The Journal of investigative dermatology 142(6): 1629-1638.e6 (Journal)
- Registered Authors
- Coucke, Paul, Willaert, Andy
- Keywords
- none
- MeSH Terms
-
- ATP-Binding Cassette Transporters/genetics
- Animals
- Core Binding Factor Alpha 1 Subunit/metabolism
- DNA Damage
- Humans
- MicroRNAs*
- Minocycline/pharmacology
- Minocycline/therapeutic use
- Mixed Function Oxygenases/metabolism
- Multidrug Resistance-Associated Proteins/genetics
- Proto-Oncogene Proteins/metabolism
- Pseudoxanthoma Elasticum*/drug therapy
- Pseudoxanthoma Elasticum*/genetics
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins/genetics
- PubMed
- 34742705 Full text @ J. Invest. Dermatol.
Citation
Nollet, L., Van Gils, M., Willaert, A., Coucke, P.J., Vanakker, O.M. (2021) Minocycline attenuates excessive DNA damage response and reduces ectopic calcification in pseudoxanthoma elasticum. The Journal of investigative dermatology. 142(6):1629-1638.e6.
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 poly(ADP-ribose) polymerase 1 (PARP1), was shown to be involved in aberrant mineralization raising the hypothesis that excessive DDR/PARP1 signaling also contributes to PXE pathogenesis. Using PXE patient and control fibroblasts, (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. Additionally, PARP1 downstream targets IL-6, STAT1/3, TET1 and RUNX2 were upregulated while 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 demonstrated the involvement of excessive DDR/PARP1 signaling in PXE pathophysiology, identifying a STAT-driven cascade resulting in increased expression of the epigenetic modifier TET1 and pro-calcifying 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 novel therapeutic compound for PXE.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping