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Originally published online as doi:10.2353/ajpath.2008.070753 on January 10, 2008

Published online before print January 10, 2008
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(American Journal of Pathology. 2008;172:440-453.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070753

Vanin-1 Pantetheinase Drives Increased Chondrogenic Potential of Mesenchymal Precursors in ank/ank Mice

Kristen A. Johnson*, Wei Yao{dagger}, Nancy E. Lane{dagger}, Philippe Naquet{ddagger} and Robert A. Terkeltaub*

From the San Diego Veterans Administration Healthcare System and Department of Medicine,*University of California San Diego, San Diego, California; the Aging Center,{dagger}Medicine and Rheumatology, University of California at Davis Medical Center, Davis, California; and the Centre d’Immunologie de Marseille-Luminy,{ddagger}Aix-Marseille Universite 13288, INSERM U631, UMR 6546, Marseille, France

Widespread endochondral and intramembranous ectopic bone formation is mediated by extracellular PPi deficiency that develops in ank/ank mice. Herein we report on the rapid condensation into chondrogenic nodules of cultured ank/ank bone marrow stromal cells (BMSCs). We compared the roles of increased chondrogenic potential versus altered osteoblast function in the ank/ank phenotype. To do so, we crossbred ank/ank mice with mice lacking Vanin-1 pantetheinase, which inhibits synthesis of the chondrogenesis regulator glutathione, since we observed increased Vanin-1 expression and pantetheinase activity and decreased glutathione in ank/ank BMSCs. Vnn1–/– BMSCs demonstrated delayed chondrogenesis mediated by increased glutathione. Moreover, increased chondrogenesis of ank/ank BMSCs and increased chondrogenic transdifferentiation and calcification by ank/ank aortic smooth muscle cells and explants were corrected by Vanin-1 knockout. Osteoblastogenesis was accelerated in ank/ank mesenchymal stem cells. However, in cultured ank/ank osteoblasts, Vanin-1 knockout actually increased specific alkaline phosphatase activity and lowered extracellular PPi, and did not correct increased calcification. Moreover, Vanin-1 knockout failed to correct the ank/ank skeletal soft tissue phenotype. Therefore, ank/ank periskeletal soft tissue calcification appears more dependent on altered osteoblastic function than enhanced chondrogenic potential and is not dependent on Vanin-1; however, Vanin-1 regulates chondrogenesis via glutathione metabolism and is critical for accelerated chondrogenesis of ank/ank mesenchymal precursors and Pi donor-driven chondrogenic transdifferentiation and calcification of aortic smooth muscle cells.






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