| First Author | Johnson K | Year | 2005 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 25 |
| Issue | 4 | Pages | 686-91 |
| PubMed ID | 15625282 | Mgi Jnum | J:110028 |
| Mgi Id | MGI:3630246 | Doi | 10.1161/01.ATV.0000154774.71187.f0 |
| Citation | Johnson K, et al. (2005) Chondrogenesis mediated by PPi depletion promotes spontaneous aortic calcification in NPP1-/- mice. Arterioscler Thromb Vasc Biol 25(4):686-91 |
| abstractText | 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. |
