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

<jats:p> <jats:bold> <jats:italic>Objective—</jats:italic> </jats:bold> 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 <jats:sub>i</jats:sub> , 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 <jats:sub>i</jats:sub> deficiencies regulate cell phenotype plasticity to promote artery calcification. </jats:p> <jats:p> <jats:bold> <jats:italic>Methods and Results—</jats:italic> </jats:bold> Using cultured multipotential NPP1−/− mouse bone marrow stromal cells, we demonstrated spontaneous chondrogenesis inhibitable by treatment with exogenous PP <jats:sub>i</jats:sub> . 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 <jats:italic>ank/ank</jats:italic> mice, which are extracellular PP <jats:sub>i</jats:sub> –depleted because of defective ANK transmembrane PP <jats:sub>i</jats:sub> transport activity. Moreover, NPP1−/− and <jats:italic>ank/ank</jats:italic> mice demonstrated aortic media calcification by von Kossa staining, and intra-aortic cartilage-specific collagen gene expression was demonstrated in situ in NPP1−/− mice. </jats:p> <jats:p> <jats:bold> <jats:italic>Conclusions—</jats:italic> </jats:bold> NPP1 and PP <jats:sub>i</jats:sub> deficiencies modulate phenotype plasticity in artery SMCs and chondrogenesis in mesenchymal precursors, thereby stimulating artery calcification by modulating cell differentiation. </jats:p>