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Endocrinology Vol. 139, No. 3 1329-1337
Copyright © 1998 by The Endocrine Society

ARTICLES

Identity of Osteoclastogenesis Inhibitory Factor (OCIF) and Osteoprotegerin (OPG): A Mechanism by which OPG/OCIF Inhibits Osteoclastogenesis in Vitro1

Hisataka Yasuda, Nobuyuki Shima, Nobuaki Nakagawa, Shin-Ichi Mochizuki, Kazuki Yano, Nobuaki Fujise, Yasushi Sato, Masaaki Goto, Kyoji Yamaguchi, Masayoshi Kuriyama, Takeshi Kanno, Akihiko Murakami, Eisuke Tsuda, Tomonori Morinaga and Kanji Higashio

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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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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 EndocrinologyHome page
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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 J. Immunol.Home page
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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 J. Clin. Endocrinol. Metab.Home page
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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 Infect. Immun.Home page
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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 EndocrinologyHome page
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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 JDRHome page
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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 Ann Rheum DisHome page
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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 EndocrinologyHome page
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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 JEMHome page
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 14, 2000; 192(4): 463 - 474.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
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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 Am. J. Pathol.Home page
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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 J. Clin. Endocrinol. Metab.Home page
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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 J. Biol. Chem.Home page
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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 JEMHome page
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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 EndocrinologyHome page
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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 Ann Rheum DisHome page
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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 JEMHome page
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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 Genes Dev.Home page
G. Karsenty
The genetic transformation of bone biology
Genes & Dev., December 1, 1999; 13(23): 3037 - 3051.
[Full Text]

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 EndocrinologyHome page
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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 EndocrinologyHome page
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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 EndocrinologyHome page
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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 Genes Dev.Home page
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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 EndocrinologyHome page
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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 EndocrinologyHome page
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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 Endocr. Rev.Home page
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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 ADRHome page
C. Minkin and V.C. Marinho
Role of the Osteoclast at the Bone-Implant Interface
Advances in Dental Research, June 1, 1999; 13(1): 49 - 56.
[Abstract] [PDF]

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 J. Biol. Chem.Home page
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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 JCBHome page
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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 Proc. Natl. Acad. Sci. USAHome page
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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 EndocrinologyHome page
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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 J. Immunol.Home page
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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 J. Biol. Chem.Home page
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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 J. Biol. Chem.Home page
H. Takai, M. Kanematsu, K. Yano, E. Tsuda, K. Higashio, K. Ikeda, K. Watanabe, and Y. Yamada
Transforming Growth Factor-beta Stimulates the Production of Osteoprotegerin/Osteoclastogenesis Inhibitory Factor by Bone Marrow Stromal Cells
J. Biol. Chem., October 16, 1998; 273(42): 27091 - 27096.
[Abstract] [Full Text] [PDF]


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