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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 fromank/ank mice, which are extracellular PPi –depleted because of defective ANK transmembrane PPi transport activity. Moreover, NPP1−/− andank/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.

Chondrogenesis Mediated by PP i Depletion Promotes Spontaneous Aortic Calcification in NPP1−/− Mice

Chondrogenesis Mediated by PP _i Depletion Promotes Spontaneous Aortic Calcification in NPP1−/− Mice