Chondrogenesis mediated by PPi depletion promotes spontaneous aortic calcification in NPP1-/- mice.

Authors: Johnson, Kristen  Polewski, Monika  van Etten, Deborah  Terkeltaub, Robert 
Citation: Johnson K, etal., Arterioscler Thromb Vasc Biol. 2005 Apr;25(4):686-91. Epub 2004 Dec 29.
Pubmed: (View Article at PubMed) PMID:15625282
DOI: Full-text: DOI:10.1161/01.ATV.0000154774.71187.f0

OBJECTIVE: We recently linked human arterial media calcification of infancy to heritable PC-1/nucleotide pyrophosphatase phosphodiesterase 1 (NPP1) deficiency. NPP1 hydrolyzes ATP to generate PP(i), a physicochemical inhibitor of hydroxyapatite crystal growth. But pathologic calcification in NPP1 deficiency states is tissue-restricted and in perispinal ligaments is endochondral differentiation-mediated rather than simply a dystrophic process. Because ectopic chondro-osseous differentiation promotes artery calcification in atherosclerosis and other disorders, we tested the hypothesis that NPP1 and PP(i) deficiencies regulate cell phenotype plasticity to promote artery calcification.
METHODS AND RESULTS: Using cultured multipotential NPP1-/- mouse bone marrow stromal cells, we demonstrated spontaneous chondrogenesis inhibitable by treatment with exogenous PP(i). We also demonstrated cartilage-specific gene expression, upregulated alkaline phosphatase, decreased expression of the physiological calcification inhibitor osteopontin, and increased calcification in NPP1-/- aortic smooth muscle cells (SMCs). Similar changes were demonstrated in aortic SMCs from ank/ank mice, which are extracellular PP(i)-depleted because of defective ANK transmembrane PP(i) transport activity. Moreover, NPP1-/- and ank/ank mice demonstrated aortic media calcification by von Kossa staining, and intra-aortic cartilage-specific collagen gene expression was demonstrated in situ in NPP1-/- mice.
CONCLUSIONS: NPP1 and PP(i) deficiencies modulate phenotype plasticity in artery SMCs and chondrogenesis in mesenchymal precursors, thereby stimulating artery calcification by modulating cell differentiation.


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CRRD Object Information
CRRD ID: 13204716
Created: 2017-07-14
Species: All species
Last Modified: 2017-07-14
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.