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.

Annotation

Disease Annotations
Objects Annotated

Additional Information

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



NHLBI Logo

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