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.
Highlights
Ectopic calcification is characterized by an abnormal deposition of calcium hydroxyapatite crystals in soft tissues including skin, eyes and blood vessels [1]
Ectopic disEctopic calcification calcificationisisaafrequently frequentlyencountered encounteredpathomechanism pathomechanisminincommon common disororders such as diabetes mellitus, chronic kidney disease (CKD) and premature ageing. It results in ders such as diabetes mellitus, CKD and premature ageing
It results in substansubstantial morbidity and mortality, no effective treatment options capable of halting the tial morbidity and mortality, no effective treatment options capable of halting the progression of ectopic calcification or reversing already existing calcium crystal deposits in humans exist to date
Summary
Elise Bouderlique 1,† , Lukas Nollet 2,3,4,† , Emmanuel Letavernier 1,‡ and Olivier M. E.L. and O.M.V. should be considered joint senior author
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