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RANK Is the Essential Signaling Receptor for Osteoclast Differentiation Factor in Osteoclastogenesis☆,☆☆

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Abstract

Osteoclast differentiation factor (ODF) is a ligand for osteoclastogenesis-inhibitory factor/osteoprotegerin (OCIF/OPG), and mediates an essential signal for osteoclastogenesis. Soluble-form ODF binds directly to osteoclast progenitors, suggesting the presence of a membrane-bound receptor for ODF (ODFR) on the cells. To understand the ODF-mediated signal transduction mechanism in osteoclastogenesis, we molecularly cloned ODFR from a mouse macrophage-like osteoclast progenitor cell line, C7. Nucleotide sequence analysis revealed that ODFR is identical to RANK, a recently identified member of the tumor necrosis factor receptor (TNFR) family, which is involved in the regulation of dendritic cell function. A polyclonal antibody against the extracellular domain of RANK induced osteoclastogenesis in the presence of macrophage colony-stimulating factor (M-CSF). In contrast, both a genetically engineered soluble RANK and Fab fragment of the antibody blocked the binding of ODF to RANK and ODF-mediated osteoclastogenesis. These results indicate that RANK is the signaling receptor essential for ODF-mediated osteoclastogenesis.

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    ☆

    Abbreviations used: ODF, osteoclast differentiation factor; OCIF, osteoclastogenesis-inhibitory factor; OPG, osteoprotegerin; TNF, tumor necrosis factor; M-CSF, macrophage colony-stimulating factor; OCL, osteoclast-like cell; 1,25(OH)2D3, 1,25-dihydroxyvitamin D3; PTH, parathyroid hormone; PGE2, prostaglandin E2; IL, interleukin; sODF, soluble ODF; sRANK, soluble RANK; RANK-Ab, anti-RANK polyclonal antibody; Fab-RANK, Fab fragment of RANK-Ab; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; TRAP, tartrate-resistant acid phosphatase

    ☆☆

    Bilezikian, J. P.Raisz, L. G.Rodan, G. A.

    1

    These authors contributed equally to this work.

    2

    To whom correspondence should be addressed. Fax: 81-285-53-1314. E-mail:[email protected].

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