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Minocycline Counteracts Ectopic Calcification in a Murine Model of Pseudoxanthoma Elasticum: A Proof-of-Concept Study
Elise Bouderlique1, Lukas Nollet2,3,4, Emmanuel Letavernier1
1UMR S 1155, Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université, 75020 Paris, France.
Abstract:
Pseudoxanthoma elasticum (PXE) is an intractable Mendelian disease characterized by ectopic calcification in skin, eyes and blood vessels. Recently, increased activation of the DNA damage response (DDR) was shown to be involved in PXE pathogenesis, while the DDR/PARP1 inhibitor minocycline was found to attenuate aberrant mineralization in PXE cells and zebrafish. In this proof-of-concept study, we evaluated the anticalcifying properties of minocycline in Abcc6 mice, an established mammalian PXE model. Abcc6 mice received oral minocycline supplementation (40 mg/kg/day) from 12 to 36 weeks of age and were compared to untreated Abcc6 and Abcc6 siblings. Ectopic calcification was evaluated using X-ray microtomography with three-dimensional reconstruction of calcium deposits in muzzle skin and Yasue's calcium staining. Immunohistochemistry for the key DDR marker H2AX was also performed. Following minocycline treatment, ectopic calcification in Abcc6 mice was significantly reduced (-43.4%, p < 0.0001) compared to untreated Abcc6 littermates. H2AX immunostaining revealed activation of the DDR at sites of aberrant mineralization in untreated Abcc6 animals. In conclusion, we validated the anticalcifying effect of minocycline in Abcc6 mice for the first time. Considering its favorable safety profile in humans and low cost as a generic drug, minocycline may be a promising therapeutic compound for PXE patients.
Insights
Minocycline significantly reduced ectopic calcification in Pseudoxanthoma elasticum (PXE) mice by 43.4%. This study validates minocycline as a potential therapeutic for PXE, an intractable genetic disorder.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Pseudoxanthoma elasticum (PXE) is a genetic disorder causing ectopic calcification.
- Increased DNA damage response (DDR) activation is implicated in PXE pathogenesis.
- Minocycline, a DDR/PARP1 inhibitor, previously showed potential in PXE models.
Purpose of the Study:
- To evaluate the anticalcifying efficacy of minocycline in a mammalian model of PXE (Abcc6 mice).
- To investigate the role of DDR in PXE pathology.
- To assess minocycline's potential as a therapeutic agent for PXE.
Main Methods:
- Oral administration of minocycline (40 mg/kg/day) to Abcc6 mice from 12 to 36 weeks of age.
- Assessment of ectopic calcification using X-ray microtomography and calcium staining.
- Immunohistochemical analysis of the DDR marker H2AX.
Main Results:
- Minocycline treatment significantly reduced ectopic calcification in Abcc6 mice by 43.4% (p < 0.0001).
- Activated DDR, indicated by H2AX staining, was observed at sites of calcification in untreated Abcc6 mice.
- Minocycline demonstrated anticalcifying properties in this PXE mouse model.
Conclusions:
- Minocycline effectively reduces ectopic calcification in Abcc6 mice, validating its anticalcifying effect in a mammalian PXE model.
- The findings support minocycline's potential as a safe, cost-effective therapeutic for PXE patients.
- Targeting DDR may be a viable strategy for treating PXE.
