Oligodeoxynucleotide targeted to the α(v) gene inhibits α(v) integrin synthesis, impairs osteoclast function, and activates intracellular signals to apoptosis

Ida Villanova, Paul A. Townsend, Eugen Uhlmann, Jochen Knolle, Anusch Peyman, Michael Amling, Roland Baron, Michael A. Horton, Anna Teti

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The α(v) integrin subunit is highly expressed in osteoclasts where it dimerizes with β1 and β3 subunits to form receptors for vitronectin and bone sialoproteins. Inhibition of osteoclast adhesion and function has previously been achieved by α(v)β3 antibodies or Arg-Gly-Asp-containing peptides which have the disadvantages of blocking a single receptor type, or of being rather nonspecific, respectively. Here we show that α(v) integrin expression in rabbit osteoclasts can be inhibited by partially phosphorothionated antisense oligodeoxynucleotide (ODN) spanning the adenine- uracil-guanine (AUG) translational start site of the human/rabbit α(v) gene, a procedure which offers the advantage of affecting all the α(v) receptors with high efficiency. The α(v) antisense ODN caused a dose-dependent, substrate-specific reduction of osteoclast adhesion and bone resorption. Control ODNs, such as sense, inverted, and mismatch, were without effect, providing evidence of specificity of the antisense reagent. It is likely as a consequence of loss of substrate interaction, the antisense ODN induced osteoclast retraction and apoptosis, increase of the cyclin/cyclin-dependent kinase complex inhibitor p21(WAF1/CIP1), and inhibition of the cell survival gene, bcl-2. Although the expression of the cell death-promoting gene, bax, remained unchanged, a reduction of the bcl-2/bax ratio, known to underlie the intracellular signal to apoptosis, was observed. This finding led us to hypothesize that these changes could provide a link between reduction of α(v) synthesis and osteoclast programmed death. In conclusion, this study provides novel insights into the use of α(v) antisense ODN as an efficacious mechanism for blocking osteoclast function and underscores for the first time the involvement of integrins in bone cell apoptosis. In vivo studies may verify potential application of this ODN as alternative therapy for bone diseases.
    Original languageEnglish
    Pages (from-to)1867-1879
    Number of pages12
    JournalJournal of Bone and Mineral Research
    Volume14
    Issue number11
    DOIs
    Publication statusPublished - 1999

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