on December 29, 2004
Published online before print December 29, 2004, doi: 10.1161/01.ATV.0000154774.71187.f0
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Submitted on October 14, 2004
Accepted on December 17, 2004
Chondrogenesis Mediated by PPi Depletion Promotes Spontaneous Aortic Calcification in NPP1-/- Mice
Kristen Johnson ;
From Rheumatology/Medicine, Veterans Affairs Medical Center/University of California at San Diego, School of Medicine.
* To whom correspondence should be addressed. E-mail: rterkeltaub{at}ucsd.edu.
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 PPi, 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 PPi 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 PPi. 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 PPi-depleted because of defective ANK transmembrane PPi 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 PPi deficiencies modulate phenotype plasticity in artery SMCs and chondrogenesis in mesenchymal precursors, thereby stimulating artery calcification by modulating cell differentiation.
Key words: nucleotide pyrophosphatase phosphodiesterase 1 • osteopontin • vascular smooth muscle cells • ank/ank
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