Role of the progressive ankylosis gene (ank) in cartilage mineralization

Wei Wang, Jinping Xu, Bin Du, Thorsten Kirsch

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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 (P i) 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, P i-mediated upregulation of APase gene expression and activity, further hydrolysis and removal of the mineralization inhibitor PPi, and subsequent mineralization.

    Original languageEnglish (US)
    Pages (from-to)312-323
    Number of pages12
    JournalMolecular and cellular biology
    Volume25
    Issue number1
    DOIs
    StatePublished - Jan 2005

    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

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