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Research Institute of Life Science, Snow Brand Milk Products Co., Ltd., 519 Ishibashi-machi, Shimotsuga-gun, Tochigi, 329–0512, Japan
Address all correspondence and requests for reprints to: Hisataka Yasuda, Research Institute of Life Science, Snow Brand Milk Products Co., Ltd., 519 Ishibashi-machi, Shimotsuga-gun, Tochigi, 329–0512, Japan. E-mail: fvbd7042{at}mb.infoweb.or.jp
The morphogenesis and remodeling of bone depends on the integrated activity of osteoblasts that form bone and osteoclasts that resorb bone. We previously reported the isolation of a new cytokine termed osteoclastogenesis inhibitory factor, OCIF, which specifically inhibits osteoclast development. Here we report the cloning of a complementary DNA of human OCIF. OCIF is identical to osteoprotegerin (OPG), a soluble member of the tumor-necrosis factor receptor family that inhibits osteoclastogenesis. Recombinant human OPG/OCIF specifically acts on bone tissues and increases bone mineral density and bone volume associated with a decrease of active osteoclast number in normal rats. Osteoblasts or bone marrow-derived stromal cells support osteoclastogenesis through cell-to-cell interactions. A single class of high affinity binding sites for OPG/OCIF appears on a mouse stromal cell line, ST2, in response to 1,25-dihydroxyvitamin D3. An anti-OPG/OCIF antibody that blocks the binding abolishes the biological activity of OPG/OCIF. When the sites are blocked with OPG/OCIF, ST2 cells fail to support osteoclastogenesis. These results suggest that the sites are involved in cell-to-cell signaling between stromal cells and osteoclast progenitors and that OPG/OCIF inhibits osteoclastogenesis by interrupting the signaling through the sites.
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 T N Crotti, M D Smith, H Weedon, M J Ahern, D M Findlay, M Kraan, P P Tak, and D R Haynes Receptor activator NF-{kappa}B ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis Ann Rheum Dis, December 1, 2002; 61(12): 1047 - 1054. [Abstract] [Full Text] [PDF]
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M. Schoppet, K. T. Preissner, and L. C. Hofbauer RANK Ligand and Osteoprotegerin: Paracrine Regulators of Bone Metabolism and Vascular Function Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 549 - 553. [Abstract] [Full Text] [PDF]
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S. Ito, K. Wakabayashi, O. Ubukata, S. Hayashi, F. Okada, and T. Hata Crystal Structure of the Extracellular Domain of Mouse RANK Ligand at 2.2-A Resolution J. Biol. Chem., February 15, 2002; 277(8): 6631 - 6636. [Abstract] [Full Text] [PDF]
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 A. R. Pettit, H. Ji, D. von Stechow, R. Muller, S. R. Goldring, Y. Choi, C. Benoist, and E. M. Gravallese TRANCE/RANKL Knockout Mice Are Protected from Bone Erosion in a Serum Transfer Model of Arthritis Am. J. Pathol., November 1, 2001; 159(5): 1689 - 1699. [Abstract] [Full Text] [PDF]
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P. A. Price, H. H. June, J. R. Buckley, and M. K. Williamson Osteoprotegerin Inhibits Artery Calcification Induced by Warfarin and by Vitamin D Arterioscler Thromb Vasc Biol, October 1, 2001; 21(10): 1610 - 1616. [Abstract] [Full Text] [PDF]
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 J. M. Brown, R. L. Vessella, P. J. Kostenuik, C. R. Dunstan, P. H. Lange, and E. Corey Serum Osteoprotegerin Levels Are Increased in Patients with Advanced Prostate Cancer Clin. Cancer Res., October 1, 2001; 7(10): 2977 - 2983. [Abstract] [Full Text] [PDF]
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Y. L. Ma, R. L. Cain, D. L. Halladay, X. Yang, Q. Zeng, R. R. Miles, S. Chandrasekhar, T. J. Martin, and J. E. Onyia Catabolic Effects of Continuous Human PTH (1-38) in Vivo Is Associated with Sustained Stimulation of RANKL and Inhibition of Osteoprotegerin and Gene-Associated Bone Formation Endocrinology, September 1, 2001; 142(9): 4047 - 4054. [Abstract] [Full Text] [PDF]
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T. Yamagishi, E. Otsuka, and H. Hagiwara Reciprocal Control of Expression of mRNAs for Osteoclast Differentiation Factor and OPG in Osteogenic Stromal Cells by Genistein: Evidence for the Involvement of Topoisomerase II in Osteoclastogenesis Endocrinology, August 1, 2001; 142(8): 3632 - 3637. [Abstract] [Full Text] [PDF]
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K. Itoh, N. Udagawa, T. Katagiri, S. Iemura, N. Ueno, H. Yasuda, K. Higashio, J. M. W. Quinn, M. T. Gillespie, T. J. Martin, et al. Bone Morphogenetic Protein 2 Stimulates Osteoclast Differentiation and Survival Supported by Receptor Activator of Nuclear Factor-{kappa}B Ligand Endocrinology, August 1, 2001; 142(8): 3656 - 3662. [Abstract] [Full Text] [PDF]
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 D. Furuya, R. Kaneko, A. Yagihashi, T. Endoh, T. Yajima, D. Kobayashi, K. Yano, E. Tsuda, and N. Watanabe Immuno-PCR Assay for Homodimeric Osteoprotegerin Clin. Chem., August 1, 2001; 47(8): 1475 - 1477. [Full Text] [PDF]
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T. Yamane, T. Kunisada, H. Tsukamoto, H. Yamazaki, H. Niwa, S. Takada, and S.-I. Hayashi Wnt Signaling Regulates Hemopoiesis Through Stromal Cells J. Immunol., July 15, 2001; 167(2): 765 - 772. [Abstract] [Full Text] [PDF]
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P. Szulc, L. C. Hofbauer, A. E. Heufelder, S. Roth, and P. D. Delmas Osteoprotegerin Serum Levels in Men: Correlation with Age, Estrogen, and Testosterone Status J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3162 - 3165. [Abstract] [Full Text] [PDF]
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M. Saika, D. Inoue, S. Kido, and T. Matsumoto 17{beta}-Estradiol Stimulates Expression of Osteoprotegerin by a Mouse Stromal Cell Line, ST-2, via Estrogen Receptor-{{alpha}} Endocrinology, June 1, 2001; 142(6): 2205 - 2212. [Abstract] [Full Text] [PDF]
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T. Ikeda, M. Kasai, M. Utsuyama, and K. Hirokawa Determination of Three Isoforms of the Receptor Activator of Nuclear Factor-{{kappa}}B Ligand and Their Differential Expression in Bone and Thymus Endocrinology, April 1, 2001; 142(4): 1419 - 1426. [Abstract] [Full Text]
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D. Chen, N. A. Sarikaya, H. Gunn, S. W. Martin, and J. D. Young ELISA Methodology for Detection of Modified Osteoprotegerin in Clinical Studies Clin. Chem., April 1, 2001; 47(4): 747 - 749. [Full Text] [PDF]
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N. Sasaki, E. Kusano, Y. Ando, K. Yano, E. Tsuda, and Y. Asano Glucocorticoid decreases circulating osteoprotegerin (OPG): possible mechanism for glucocorticoid induced osteoporosis Nephrol. Dial. Transplant., March 1, 2001; 16(3): 479 - 482. [Abstract] [Full Text] [PDF]
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Y. Asou, S. R. Rittling, H. Yoshitake, K. Tsuji, K. Shinomiya, A. Nifuji, D. T. Denhardt, and M. Noda Osteopontin Facilitates Angiogenesis, Accumulation of Osteoclasts, and Resorption in Ectopic Bone Endocrinology, March 1, 2001; 142(3): 1325 - 1332. [Abstract] [Full Text] [PDF]
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R. Wang, L. Zhang, X. Zhang, J. Moreno, X. Luo, M. Tondravi, and Y. Shi Differential Regulation of the Expression of CD95 Ligand, Receptor Activator of Nuclear Factor-{{kappa}}B Ligand (RANKL), TNF-Related Apoptosis-Inducing Ligand (TRAIL), and TNF-{{alpha}} During T Cell Activation J. Immunol., February 1, 2001; 166(3): 1983 - 1990. [Abstract] [Full Text] [PDF]
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R. J. Leach, F. R. Singer, and G. D. Roodman The Genetics of Paget's Disease of the Bone J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 24 - 28. [Full Text]
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Y. Sakuma, K. Tanaka, M. Suda, Y. Komatsu, A. Yasoda, M. Miura, A. Ozasa, S. Narumiya, Y. Sugimoto, A. Ichikawa, et al. Impaired Bone Resorption by Lipopolysaccharide In Vivo in Mice Deficient in the Prostaglandin E Receptor EP4 Subtype Infect. Immun., December 1, 2000; 68(12): 6819 - 6825. [Abstract] [Full Text] [PDF]
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M. Takami, N. Takahashi, N. Udagawa, C. Miyaura, K. Suda, J.-T. Woo, T. J. Martin, K. Nagai, and T. Suda Intracellular Calcium and Protein Kinase C Mediate Expression of Receptor Activator of Nuclear Factor-{{kappa}}B Ligand and Osteoprotegerin in Osteoblasts Endocrinology, December 1, 2000; 141(12): 4711 - 4719. [Abstract] [Full Text] [PDF]
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G.E. Wise, S.J. Lumpkin, H. Huang, and Q. Zhang Osteoprotegerin and Osteoclast Differentiation Factor in Tooth Eruption Journal of Dental Research, December 1, 2000; 79(12): 1937 - 1942. [Abstract] [PDF]
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S. R Goldring The final pathogenetic steps in focal bone erosions in rheumatoid arthritis Ann Rheum Dis, November 1, 2000; 59(90001): i72 - 74. [Full Text] [PDF]
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N. Udagawa, N. Takahashi, H. Yasuda, A. Mizuno, K. Itoh, Y. Ueno, T. Shinki, M. T. Gillespie, T. J. Martin, K. Higashio, et al. Osteoprotegerin Produced by Osteoblasts Is an Important Regulator in Osteoclast Development and Function Endocrinology, September 1, 2000; 141(9): 3478 - 3484. [Abstract] [Full Text] [PDF]
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H. Min, S. Morony, I. Sarosi, C. R. Dunstan, C. Capparelli, S. Scully, G. Van, S. Kaufman, P. J. Kostenuik, D. L. Lacey, et al. Osteoprotegerin Reverses Osteoporosis by Inhibiting Endosteal Osteoclasts and Prevents Vascular Calcification by Blocking a Process Resembling Osteoclastogenesis J. Exp. Med., August 21, 2000; 192(4): 463 - 474. [Abstract] [Full Text] [PDF]
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A. Yamaguchi, T. Komori, and T. Suda Regulation of Osteoblast Differentiation Mediated by Bone Morphogenetic Proteins, Hedgehogs, and Cbfa1 Endocr. Rev., August 1, 2000; 21(4): 393 - 411. [Abstract] [Full Text] [PDF]
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D. L. Lacey, H. L. Tan, J. Lu, S. Kaufman, G. Van, W. Qiu, A. Rattan, S. Scully, F. Fletcher, T. Juan, et al. Osteoprotegerin Ligand Modulates Murine Osteoclast Survival in Vitro and in Vivo Am. J. Pathol., August 1, 2000; 157(2): 435 - 448. [Abstract] [Full Text] [PDF]
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L. C. Hofbauer and A. E. Heufelder The Role of Receptor Activator of Nuclear Factor-{kappa}B Ligand and Osteoprotegerin in the Pathogenesis and Treatment of Metabolic Bone Diseases J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2355 - 2363. [Full Text]
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H. Mano, C. Kimura, Y. Fujisawa, T. Kameda, M. Watanabe-Mano, H. Kaneko, T. Kaneda, Y. Hakeda, and M. Kumegawa Cloning and Function of Rabbit Peroxisome Proliferator-activated Receptor delta /beta in Mature Osteoclasts J. Biol. Chem., March 10, 2000; 275(11): 8126 - 8132. [Abstract] [Full Text] [PDF]
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K. Kobayashi, N. Takahashi, E. Jimi, N. Udagawa, M. Takami, S. Kotake, N. Nakagawa, M. Kinosaki, K. Yamaguchi, N. Shima, et al. Tumor Necrosis Factor {alpha} Stimulates Osteoclast Differentiation by a Mechanism Independent of the Odf/Rankl-Rank Interaction J. Exp. Med., January 17, 2000; 191(2): 275 - 286. [Abstract] [Full Text] [PDF]
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T. Yamashita, H. Yoshitake, K. Tsuji, N. Kawaguchi, Y.-i. Nabeshima, and M. Noda Retardation in Bone Resorption after Bone Marrow Ablation in Klotho Mutant Mice Endocrinology, January 1, 2000; 141(1): 438 - 445. [Abstract] [Full Text] [PDF]
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I Itonaga, A Sabokbar, D W Murray, and N A Athanasou Effect of osteoprotegerin and osteoprotegerin ligand on osteoclast formation by arthroplasty membrane derived macrophages Ann Rheum Dis, January 1, 2000; 59(1): 26 - 31. [Abstract] [Full Text]
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F. Arai, T. Miyamoto, O. Ohneda, T. Inada, T. Sudo, K. Brasel, T. Miyata, D. M. Anderson, and T. Suda Commitment and Differentiation of Osteoclast Precursor Cells by the Sequential Expression of C-Fms and Receptor Activator of Nuclear Factor {kappa}b (Rank) Receptors J. Exp. Med., December 20, 1999; 190(12): 1741 - 1754. [Abstract] [Full Text] [PDF]
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R. Okazaki, M. Toriumi, S. Fukumoto, M. Miyamoto, T. Fujita, K. Tanaka, and Y. Takeuchi Thiazolidinediones Inhibit Osteoclast-Like Cell Formation and Bone Resorption in Vitro Endocrinology, November 1, 1999; 140(11): 5060 - 5065. [Abstract] [Full Text]
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L. C. Hofbauer, F. Gori, B. L. Riggs, D. L. Lacey, C. R. Dunstan, T. C. Spelsberg, and S. Khosla Stimulation of Osteoprotegerin Ligand and Inhibition of Osteoprotegerin Production by Glucocorticoids in Human Osteoblastic Lineage Cells: Potential Paracrine Mechanisms of Glucocorticoid-Induced Osteoporosis Endocrinology, October 1, 1999; 140(10): 4382 - 4389. [Abstract] [Full Text]
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R. J. Thomas, T. A. Guise, J. J. Yin, J. Elliott, N. J. Horwood, T. J. Martin, and M. T. Gillespie Breast Cancer Cells Interact with Osteoblasts to Support Osteoclast Formation Endocrinology, October 1, 1999; 140(10): 4451 - 4458. [Abstract] [Full Text]
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W. C. Dougall, M. Glaccum, K. Charrier, K. Rohrbach, K. Brasel, T. De Smedt, E. Daro, J. Smith, M. E. Tometsko, C. R. Maliszewski, et al. RANK is essential for osteoclast and lymph node development Genes & Dev., September 15, 1999; 13(18): 2412 - 2424. [Abstract] [Full Text]
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S.-K. Lee and J. A. Lorenzo Parathyroid Hormone Stimulates TRANCE and Inhibits Osteoprotegerin Messenger Ribonucleic Acid Expression in Murine Bone Marrow Cultures: Correlation with Osteoclast-Like Cell Formation Endocrinology, August 1, 1999; 140(8): 3552 - 3561. [Abstract] [Full Text]
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T. A. Hentunen, S. H. Jackson, H. Chung, S. V. Reddy, J. Lorenzo, S. J. Choi, and G. D. Roodman Characterization of Immortalized Osteoclast Precursors Developed from Mice Transgenic for Both bcl-XL and Simian Virus 40 Large T Antigen Endocrinology, July 1, 1999; 140(7): 2954 - 2961. [Abstract] [Full Text]
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T. Suda, N. Takahashi, N. Udagawa, E. Jimi, M. T. Gillespie, and T. J. Martin Modulation of Osteoclast Differentiation and Function by the New Members of the Tumor Necrosis Factor Receptor and Ligand Families Endocr. Rev., June 1, 1999; 20(3): 345 - 357. [Abstract] [Full Text]
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L. Lum, B. R. Wong, R. Josien, J. D. Becherer, H. Erdjument-Bromage, J. Schlondorff, P. Tempst, Y. Choi, and C. P. Blobel Evidence for a Role of a Tumor Necrosis Factor-alpha (TNF-alpha )-converting Enzyme-like Protease in Shedding of TRANCE, a TNF Family Member Involved in Osteoclastogenesis and Dendritic Cell Survival J. Biol. Chem., May 7, 1999; 274(19): 13613 - 13618. [Abstract] [Full Text] [PDF]
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 T. L. Burgess, Y.-x. Qian, S. Kaufman, B. D. Ring, G. Van, C. Capparelli, M. Kelley, H. Hsu, W. J. Boyle, C. R. Dunstan, et al. The Ligand for Osteoprotegerin (OPGL) Directly Activates Mature Osteoclasts J. Cell Biol., May 3, 1999; 145(3): 527 - 538. [Abstract] [Full Text] [PDF]
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H. Hsu, D. L. Lacey, C. R. Dunstan, I. Solovyev, A. Colombero, E. Timms, H.-L. Tan, G. Elliott, M. J. Kelley, I. Sarosi, et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand PNAS, March 30, 1999; 96(7): 3540 - 3545. [Abstract] [Full Text] [PDF]
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I. Nakamura, H. Tanaka, G. A. Rodan, and L. T. Duong Echistatin Inhibits the Migration of Murine Prefusion Osteoclasts and the Formation of Multinucleated Osteoclast-Like Cells Endocrinology, December 1, 1998; 139(12): 5182 - 5193. [Abstract] [Full Text] [PDF]
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T. J. Yun, P. M. Chaudhary, G. L. Shu, J. K. Frazer, M. K. Ewings, S. M. Schwartz, V. Pascual, L. E. Hood, and E. A. Clark3 OPG/FDCR-1, a TNF Receptor Family Member, Is Expressed in Lymphoid Cells and Is Up-Regulated by Ligating CD40 J. Immunol., December 1, 1998; 161(11): 6113 - 6121. [Abstract] [Full Text] [PDF]
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B. R. Wong, R. Josien, S. Y. Lee, M. Vologodskaia, R. M. Steinman, and Y. Choi The TRAF Family of Signal Transducers Mediates NF-kappa B Activation by the TRANCE Receptor J. Biol. Chem., October 23, 1998; 273(43): 28355 - 28359. [Abstract] [Full Text] [PDF]
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