Abstract:
:Biallelic mutations in ABCC6 cause pseudoxanthoma elasticum (PXE), a disease characterized by calcification in the skin, eyes, and blood vessels. The function of ATP-binding cassette C6 (ABCC6) and the pathogenesis of PXE remain unclear. We used mouse models and patient fibroblasts to demonstrate genetic interaction and shared biochemical and cellular mechanisms underlying ectopic calcification in PXE and related disorders caused by defined perturbations in extracellular adenosine 5'-triphosphate catabolism. Under osteogenic culture conditions, ABCC6 mutant cells calcified, suggesting a provoked cell-autonomous defect. Using a conditional Abcc6 knockout mouse model, we excluded the prevailing pathogenic hypothesis that singularly invokes failure of hepatic secretion of an endocrine inhibitor of calcification. Instead, deficiency of Abcc6 in both local and distant cells was necessary to achieve the early onset and penetrant ectopic calcification observed upon constitutive gene targeting. ABCC6 mutant cells additionally had increased expression and activity of tissue-nonspecific alkaline phosphatase (TNAP), an enzyme that degrades pyrophosphate, a major inhibitor of calcification. A selective and orally bioavailable TNAP inhibitor prevented calcification in ABCC6 mutant cells in vitro and attenuated both the development and progression of calcification in Abcc6-/- mice in vivo, without the deleterious effects on bone associated with other proposed treatment strategies.
journal_name
Sci Transl Medjournal_title
Science translational medicineauthors
Ziegler SG,Ferreira CR,MacFarlane EG,Riddle RC,Tomlinson RE,Chew EY,Martin L,Ma CT,Sergienko E,Pinkerton AB,Millán JL,Gahl WA,Dietz HCdoi
10.1126/scitranslmed.aal1669subject
Has Abstractpub_date
2017-06-07 00:00:00issue
393eissn
1946-6234issn
1946-6242pii
9/393/eaal1669journal_volume
9pub_type
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