Progressive ankylosis protein (ank) in osteoblasts and osteoclasts controls bone formation and bone remodeling

Hyon Jong Kim, Takeshi Minashima, Edward F. McCarthy, Jeffrey A. Winkles, Thorsten Kirsch

    Research output: Contribution to journalArticle

    Abstract

    The progressive ankylosis gene (ank) encodes a transmembrane protein that transports intracellular inorganic pyrophosphate (PPi) to the extracellular milieu. ank/ank mice, which express a truncated nonfunctional ANK, showed a markedly reduced bone mass, bone-formation rate, and number of tartrate-resistant acid phosphatase-positive (TRAP+) multinucleated osteoclasts. ANK function deficiency suppressed osteoblastic differentiation of ank/ank bone marrow stromal cells, as indicated by the decrease in the expression of bone marker genes, including osterix, reduced alkaline phosphatase activity, and mineralization. Runx2 gene expression levels were not altered. Conversely, overexpression of ANK in the preosteoblastic cell line MC3T3-E1 resulted in increased expression of bone marker genes, including osterix. Whereas runx2 expression was not altered in ANK-overexpressing MC3T3-E1 cells, runx2 transcriptional activity was increased. Extracellular PPi or Pi stimulated osteoblastogenic differentiation of MC3T3-E1 cells or partially rescued delayed osteoblastogenic differentiation of ank/ank bone marrow stromal cells. A loss of PPi transport function ANK mutation also stimulated osteoblastogenic differentiation of MC3T3-E1 cells. Furthermore, ANK function deficiency suppressed the formation of multinucleated osteoclasts from ank/ank bone marrow cells cultured in the presence of macrophage colony-stimulating factor and receptor activator of nuclear factor-kB ligand. In conclusion, ANK is a positive regulator of osteoblastic and osteoclastic differentiation events toward a mature osteoblastic and osteoclastic phenotype.

    Original languageEnglish (US)
    Pages (from-to)1771-1783
    Number of pages13
    JournalJournal of Bone and Mineral Research
    Volume25
    Issue number8
    DOIs
    StatePublished - Aug 2010

    Keywords

    • Ank
    • Osteoblast differentiation
    • Osteoclast differentiation
    • Skeletal phenotype
    • Transcription factors

    ASJC Scopus subject areas

    • Endocrinology, Diabetes and Metabolism
    • Orthopedics and Sports Medicine

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