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J Vasc Res. 2011;48(3):227-35. doi: 10.1159/000318805. Epub 2010 Nov 23.

Arterial calcification is driven by RAGE in Enpp1-/- mice.

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Department of Medicine, Rheumatology Section, VA Health Care System/UCSD, San Diego, CA 92161, USA.



Ectopic osteochondral differentiation, driven by ENPP1-catalyzed generation of the chondrogenesis and calcification inhibitor inorganic pyrophosphate (PP(i)), promotes generalized arterial calcification of infancy. The multiligand receptor for advanced glycation end-products (RAGE), which promotes atherosclerosis and diabetic cardiovascular and renal complications, also mediates chondrocyte differentiation in response to RAGE ligand calgranulins such as S100A11. Here, we tested RAGE involvement in ENPP1 deficiency-associated arterial calcification.


Because ectopic artery calcification in Enpp1-/- mice is P(i)-dependent and mediated by PP(i) deficiency, in vitro studies on effects of S100A11 and RAGE on mouse aortic explants were conducted using exogenous P(i), as well as alkaline phosphatase to hydrolyze ambient PP(i).


S100A11 induced cartilage-specific collagen IX/XI expression and calcification dependent on RAGE in mouse aortic explants that was inhibited by the endogenous RAGE signaling inhibitor soluble RAGE (sRAGE). Enpp1-/- aortic explants demonstrated decreased P(i)-stimulated release of sRAGE, and increased calcification and type IX/XI collagen expression that were suppressed by exogenous sRAGE and by Rage knockout. Last, Rage knockout suppressed spontaneous aortic calcification in situ in Enpp1-/- mice.


Cultured Enpp1-/- aortic explants have decreased P(i)-stimulated release of sRAGE, and RAGE promotes ectopic chondrogenic differentiation and arterial calcification in Enpp1-/- mice.

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