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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:686.)
© 2005 American Heart Association, Inc.

Vascular Biology

Chondrogenesis Mediated by PP_i Depletion Promotes Spontaneous Aortic Calcification in NPP1–/– Mice

Kristen Johnson; Monika Polewski; Deborah van Etten; Robert Terkeltaub

From Rheumatology/Medicine, Veterans Affairs Medical Center/University of California at San Diego, School of Medicine.

Correspondence to Robert Terkeltaub, 111K, Veterans Affairs Medical Center, 3350 La Jolla Village Dr, San Diego, CA 92161. 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 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.

Human "idiopathic" infantile arterial media calcification is linked to deficient PP_i-generating PC-1/nucleotide pyrophosphatase phosphodiesterase 1 (NPP1). We demonstrate that NPP1 and extracellular PP_i deficiencies promote chondrogenic differentiation in mesenchymal precursors and vascular smooth muscle cells. Therefore, NPP1 and PP_i deficiencies promote active rather than simply dystrophic artery calcification, mediated partly by primary alterations in cell differentiation.

Key Words: nucleotide pyrophosphatase phosphodiesterase 1 • osteopontin • vascular smooth muscle cells • ank/ank

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Dwight A. Towler
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