Vanin-1 pantetheinase drives increased chondrogenic potential of mesenchymal precursors in ank/ank mice.
Widespread endochondral and intramembranous ectopic bone formation is mediated by extracellular PP(i) 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 PP(i), 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 P(i) donor-driven chondrogenic transdifferentiation and calcification of aortic smooth muscle cells.
Johnson
Kristen A
KA
Department of Medicine, University of California San Diego, San Diego, CA 92161, USA.
Yao
Wei
W
Lane
Nancy E
NE
Naquet
Philippe
P
Terkeltaub
Robert A
RA
D000469:Alkaline Phosphatase / Q000378:metabolism; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D054338:Cell Transdifferentiation / Q000502:physiology; D002478:Cells, Cultured; D020219:Chondrogenesis / Q000502:physiology*; D058851:GPI-Linked Proteins; D005978:Glutathione / Q000378:metabolism; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D009924:Organ Culture Techniques; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D028061:Phosphate Transport Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D008565:Membrane Proteins; D028061:Phosphate Transport Proteins; C410982:ank protein, mouse; D000469:Alkaline Phosphatase; D000581:Amidohydrolases; C022314:pantetheinase; D005978:Glutathione