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B Ligand Derived from Osteoblasts1
* Institute for Oral Science, Matsumoto Dental University, Nagano, Japan;
Department of Biochemistry, Matsumoto Dental University, Nagano, Japan;
Department of Pharmacology, School of Dentistry, Aichi Gakuin University, Aichi, Japan; and
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria
Osteoprotegerin (OPG) is a decoy receptor for receptor activator of NF-
B ligand (RANKL). We previously reported that OPG deficiency elevated the circulating level of RANKL in mice. Using OPG–/– mice, we investigated whether OPG is involved in the shedding of RANKL by cells expressing RANKL. Osteoblasts and activated T cells in culture released a large amount of RANKL in the absence of OPG. OPG or a soluble form of receptor activator of NF-B (the receptor of RANKL) suppressed the release of RANKL from those cells. OPG- and T cell-double-deficient mice showed an elevated serum RANKL level equivalent to that of OPG–/– mice, indicating that circulating RANKL is mainly derived from bone. The serum level of RANKL in OPG–/– mice was increased by ovariectomy or administration of 1
,25-dihydroxyvitamin D3. Expression of RANKL mRNA in bone, but not thymus or spleen, was increased in wild-type and OPG–/– mice by 1,25-dihydroxyvitamin D3. These results suggest that OPG suppresses the shedding of RANKL from osteoblasts and that the serum RANKL in OPG–/– mice exactly reflects the state of bone resorption.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by Grants-in-Aid 16390535, 07791336, and 17390497.
2 Address correspondence and reprint requests to Dr. Naoyuki Takahashi, Institute for Oral Science, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri, Nagano 399-0781, Japan. E-mail address: takahashinao{at}po.mdu.ac.jp
3 Abbreviations used in this paper: RANKL, receptor activator of NF-B ligand; 1,25(OH)2D3, 1,25-dihydroxyvitamin D3; MT-MMP, membrane-type matrix metalloproteinase; TACE, TNF--converting enzyme; TIMP, tissue inhibitor of metalloproteinase; OPG, osteoprotegerin; CRD, cysteine-rich domain; DcR3, decoy receptor 3; DR6, death receptor 6; WT, wild type; OVX, ovariectomized; siRNA, small interfering RNA; TAPI-2, TNF- protease inhibitor-2.
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