RESUMEN
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.
Asunto(s)
Minociclina/administración & dosificación , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Seudoxantoma Elástico/diagnóstico por imagen , Seudoxantoma Elástico/tratamiento farmacológico , Administración Oral , Animales , Modelos Animales de Enfermedad , Técnicas de Silenciamiento del Gen , Histonas/metabolismo , Masculino , Ratones , Minociclina/farmacología , Prueba de Estudio Conceptual , Seudoxantoma Elástico/genética , Seudoxantoma Elástico/metabolismo , Resultado del Tratamiento , Microtomografía por Rayos XRESUMEN
A neonate who received vitamin K (VK) supplementation then developed severe late-onset bleeding with abnormal prothrombin time and activated partial thromboplastine time. The bleeding was corrected after intravenous VK. Molecular analysis of the gamma-glutamylcarboxylase gene revealed a heterozygous single nucleotide polymorphism, which decreases carboxylase activity and induces VK-dependent coagulation deficiency.