Novel Treatments for PXE: Targeting the Systemic and Local Drivers of Ectopic Calcification.

Autor: Jacobs IJ; Biomedical Sciences MS Program, Jefferson College of Life Sciences, Thomas Jefferson University, Philadelphia, PA 19107, USA.; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.; PXE International Center of Excellence in Research and Clinical Care, Thomas Jefferson University, Philadelphia, PA 19107, USA., Li Q; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.; PXE International Center of Excellence in Research and Clinical Care, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2023 Oct 10; Vol. 24 (20). Date of Electronic Publication: 2023 Oct 10.
DOI: 10.3390/ijms242015041
Abstrakt: Pseudoxanthoma elasticum (PXE) is a heritable multisystem ectopic calcification disorder. The gene responsible for PXE, ABCC6 , encodes ABCC6, a hepatic efflux transporter regulating extracellular inorganic pyrophosphate (PPi), a potent endogenous calcification inhibitor. Recent studies demonstrated that in addition to the deficiency of plasma PPi, the activated DDR/PARP signaling in calcified tissues provides an additional possible mechanism of ectopic calcification in PXE. This study examined the effects of etidronate (ETD), a stable PPi analog, and its combination with minocycline (Mino), a potent inhibitor of DDR/PARP, on ectopic calcification in an Abcc6 -/- mouse model of PXE. Abcc6 -/- mice, at 4 weeks of age, before the development of ectopic calcification, were treated with ETD, Mino, or both for 18 weeks. Micro-computed tomography, histopathologic examination, and quantification of the calcium content in Abcc6 -/- mice treated with both ETD and Mino revealed further reduced calcification than either treatment alone. The effects were associated with reduced serum alkaline phosphatase activity without changes in plasma PPi concentrations. These results suggest that ETD and Mino combination therapy might provide an effective therapeutic approach for PXE, a currently intractable disease.
Databáze: MEDLINE
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