TY - JOUR
T1 - Ectopic calcification in pseudoxanthoma elasticum responds to inhibition of tissue-nonspecific alkaline phosphatase
AU - Ziegler, Shira G.
AU - Ferreira, Carlos R.
AU - Macfarlane, Elena Gallo
AU - Riddle, Ryan
AU - Tomlinson, Ryan E.
AU - Chew, Emily Y.
AU - Martin, Ludovic
AU - Ma, Chen Ting
AU - Sergienko, Eduard
AU - Pinkerton, Anthony B.
AU - Millán, José Luis
AU - Gahl, William A.
AU - Dietz, Harry C.
N1 - Publisher Copyright:
© 2017, The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
PY - 2017/6/7
Y1 - 2017/6/7
N2 - 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 tissuenonspecific 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.
AB - 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 tissuenonspecific 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.
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U2 - 10.1126/scitranslmed.aal1669
DO - 10.1126/scitranslmed.aal1669
M3 - Article
C2 - 28592560
AN - SCOPUS:85020446878
SN - 1946-6234
VL - 9
JO - Science translational medicine
JF - Science translational medicine
IS - 393
M1 - eaal1669
ER -