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Molecular and Cellular Biology, January 2005, p. 312-323, Vol. 25, No. 1
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.1.312-323.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Role of the Progressive Ankylosis Gene (ank) in Cartilage Mineralization

Wei Wang, Jinping Xu, Bin Du, and Thorsten Kirsch*

Musculoskeletal Research Laboratories, Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, Maryland

Received 13 April 2004/ Returned for modification 7 July 2004/ Accepted 1 October 2004

Mineralization of growth plate cartilage is a critical event during endochondral bone formation, which allows replacement of cartilage by bone. Ankylosis protein (Ank), which transports intracellular inorganic pyrophosphate (PPi) to the extracellular milieu, is expressed by hypertrophic and, especially highly, by terminally differentiated mineralizing growth plate chondrocytes. Blocking Ank transport activity or ank expression in terminally differentiated mineralizing growth plate chondrocytes led to increases of intra- and extracellular PPi concentrations, decreases of alkaline phosphatase (APase) expression and activity, and inhibition of mineralization, whereas treatment of these cells with the APase inhibitor levamisole led to an increase of extracellular PPi concentration and inhibition of mineralization. Ank-overexpressing hypertrophic nonmineralizing growth plate chondrocytes showed decreased intra- and extracellular PPi levels; increased mineralization-related gene expression of APase, type I collagen, and osteocalcin; increased APase activity; and mineralization. Treatment of Ank-expressing growth plate chondrocytes with a phosphate transport blocker (phosphonoformic acid [PFA]) inhibited uptake of inorganic phosphate (Pi) and gene expression of the type III Na+/Pi cotransporters Pit-1 and Pit-2. Furthermore, PFA or levamisole treatment of Ank-overexpressing hypertrophic chondrocytes inhibited APase expression and activity and subsequent mineralization. In conclusion, increased Ank activity results in elevated intracellular PPi transport to the extracellular milieu, initial hydrolysis of PPi to Pi, Pi-mediated upregulation of APase gene expression and activity, further hydrolysis and removal of the mineralization inhibitor PPi, and subsequent mineralization.

* Corresponding author. Mailing address: Department of Orthopaedics, University of Maryland School of Medicine, 22 South Greene St., Baltimore, MD 21201. Phone: (410) 706-2417. Fax: (410) 706-0028. E-mail: tkirsch{at}umoa.umm.edu.

Molecular and Cellular Biology, January 2005, p. 312-323, Vol. 25, No. 1
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.1.312-323.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • WANG, J., TSUI, H. W., BEIER, F., TSUI, F. W.L. (2009). The CPPDD-Associated ANKH M48T Mutation Interrupts the Interaction of ANKH with the Sodium/Phosphate Cotransporter PiT-1. The Journal of Rheumatology 36: 1265-1272 [Abstract] [Full Text]  
  • Johnson, K. A., Yao, W., Lane, N. E., Naquet, P., Terkeltaub, R. A. (2008). Vanin-1 Pantetheinase Drives Increased Chondrogenic Potential of Mesenchymal Precursors in ank/ank Mice. Am. J. Pathol. 172: 440-453 [Abstract] [Full Text]  
  • Addison, W. N., Azari, F., Sorensen, E. S., Kaartinen, M. T., McKee, M. D. (2007). Pyrophosphate Inhibits Mineralization of Osteoblast Cultures by Binding to Mineral, Up-regulating Osteopontin, and Inhibiting Alkaline Phosphatase Activity. J. Biol. Chem. 282: 15872-15883 [Abstract] [Full Text]  


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