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Endocrine Reviews 20 (3): 345-357
Copyright © 1999 by The Endocrine Society

Modulation of Osteoclast Differentiation and Function by the New Members of the Tumor Necrosis Factor Receptor and Ligand Families

Tatsuo Suda, Naoyuki Takahashi, Nobuyuki Udagawa, Eijiro Jimi, Matthew T. Gillespie and T. John Martin

Department of Biochemistry (T.S., N.T., N.U., E.J.), School of Dentistry, Showa University, Shinagawa-ku, Tokyo 142-8555, Japan; and St. Vincent’s Institute of Medical Research (M.T.G., T.J.M.), University of Melbourne, Fitzroy, Victoria 3065, Australia

I. Introduction
II. Role of Osteoblasts/Stromal Cells in Osteoclast Differentiation and Function
A. Origin of osteoclasts
B. Stimulation of osteoclast differentiation by osteoblasts/stromal cells
C. Stimulation of osteoclast function by osteoblasts/stromal cells
III. New Members of the Tumor Necrosis Factor (TNF) Receptor and Ligand Families
A. Osteoprotegerin (OPG)
B. Osteoclast differentiation factor (ODF) and stromal osteoclast-forming activity (SOFA)
IV. Regulatory Mechanism in Osteoclast Development and Function
A. Regulatory mechanism of osteoclast differentiation by RANKL
B. Regulatory mechanism of RANKL action on osteoclast function
C. Signals induced by interleukin-1 (IL-1) and RANKL in osteoclasts
V. Regulation of Human Osteoclast Development
VI. Summary and Conclusion




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N. Kim, Y. Kadono, M. Takami, J. Lee, S.-H. Lee, F. Okada, J. H. Kim, T. Kobayashi, P. R. Odgren, H. Nakano, et al.
Osteoclast differentiation independent of the TRANCE-RANK-TRAF6 axis
J. Exp. Med., September 6, 2005; 202(5): 589 - 595.
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 Endocr. Rev.Home page
S. Nagpal, S. Na, and R. Rathnachalam
Noncalcemic Actions of Vitamin D Receptor Ligands
Endocr. Rev., August 1, 2005; 26(5): 662 - 687.
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S. Yang, N. Takahashi, T. Yamashita, N. Sato, M. Takahashi, M. Mogi, T. Uematsu, Y. Kobayashi, Y. Nakamichi, K. Takeda, et al.
Muramyl Dipeptide Enhances Osteoclast Formation Induced by Lipopolysaccharide, IL-1{alpha}, and TNF-{alpha} through Nucleotide-Binding Oligomerization Domain 2-Mediated Signaling in Osteoblasts
J. Immunol., August 1, 2005; 175(3): 1956 - 1964.
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 BloodHome page
N. K. Lee, Y. G. Choi, J. Y. Baik, S. Y. Han, D.-w. Jeong, Y. S. Bae, N. Kim, and S. Y. Lee
A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation
Blood, August 1, 2005; 106(3): 852 - 859.
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Y. Kobayashi, I. Take, T. Yamashita, T. Mizoguchi, T. Ninomiya, T. Hattori, S. Kurihara, H. Ozawa, N. Udagawa, and N. Takahashi
Prostaglandin E2 Receptors EP2 and EP4 Are Down-regulated during Differentiation of Mouse Osteoclasts from Their Precursors
J. Biol. Chem., June 24, 2005; 280(25): 24035 - 24042.
[Abstract] [Full Text] [PDF]

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 JEMHome page
M. G. Ruocco, S. Maeda, J. M. Park, T. Lawrence, L.-C. Hsu, Y. Cao, G. Schett, E. F. Wagner, and M. Karin
I{kappa}B kinase (IKK){beta}, but not IKK{alpha}, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss
J. Exp. Med., May 16, 2005; 201(10): 1677 - 1687.
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Y. Kobayashi, T. Mizoguchi, I. Take, S. Kurihara, N. Udagawa, and N. Takahashi
Prostaglandin E2 Enhances Osteoclastic Differentiation of Precursor Cells through Protein Kinase A-dependent Phosphorylation of TAK1
J. Biol. Chem., March 25, 2005; 280(12): 11395 - 11403.
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S. D. Yogesha, S. M. Khapli, and M. R. Wani
Interleukin-3 and Granulocyte-Macrophage Colony-stimulating Factor Inhibits Tumor Necrosis Factor (TNF)-{alpha}-induced Osteoclast Differentiation by Down-regulation of Expression of TNF Receptors 1 and 2
J. Biol. Chem., March 25, 2005; 280(12): 11759 - 11769.
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T. M. Murray, L. G. Rao, P. Divieti, and F. R. Bringhurst
Parathyroid Hormone Secretion and Action: Evidence for Discrete Receptors for the Carboxyl-Terminal Region and Related Biological Actions of Carboxyl- Terminal Ligands
Endocr. Rev., February 1, 2005; 26(1): 78 - 113.
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W. Liu, D. Xu, H. Yang, H. Xu, Z. Shi, X. Cao, S. Takeshita, J. Liu, M. Teale, and X. Feng
Functional Identification of Three Receptor Activator of NF-{kappa}B Cytoplasmic Motifs Mediating Osteoclast Differentiation and Function
J. Biol. Chem., December 24, 2004; 279(52): 54759 - 54769.
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W. Gianni, A. Ricci, P. Gazzaniga, M. Brama, M. Pietropaolo, S. Votano, F. Patane, A. M. Agliano, G. Spera, V. Marigliano, et al.
Raloxifene Modulates Interleukin-6 and Tumor Necrosis Factor-{alpha} Synthesis in Vivo: Results from a Pilot Clinical Study
J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6097 - 6099.
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M. Matsumoto, M. Kogawa, S. Wada, H. Takayanagi, M. Tsujimoto, S. Katayama, K. Hisatake, and Y. Nogi
Essential Role of p38 Mitogen-activated Protein Kinase in Cathepsin K Gene Expression during Osteoclastogenesis through Association of NFATc1 and PU.1
J. Biol. Chem., October 29, 2004; 279(44): 45969 - 45979.
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T. Kukita, N. Wada, A. Kukita, T. Kakimoto, F. Sandra, K. Toh, K. Nagata, T. Iijima, M. Horiuchi, H. Matsusaki, et al.
RANKL-induced DC-STAMP Is Essential for Osteoclastogenesis
J. Exp. Med., October 4, 2004; 200(7): 941 - 946.
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N. Sato, N. Takahashi, K. Suda, M. Nakamura, M. Yamaki, T. Ninomiya, Y. Kobayashi, H. Takada, K. Shibata, M. Yamamoto, et al.
MyD88 But Not TRIF Is Essential for Osteoclastogenesis Induced by Lipopolysaccharide, Diacyl Lipopeptide, and IL-1{alpha}
J. Exp. Med., September 7, 2004; 200(5): 601 - 611.
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D. Kamei, K. Yamakawa, Y. Takegoshi, M. Mikami-Nakanishi, Y. Nakatani, S. Oh-ishi, H. Yasui, Y. Azuma, N. Hirasawa, K. Ohuchi, et al.
Reduced Pain Hypersensitivity and Inflammation in Mice Lacking Microsomal Prostaglandin E Synthase-1
J. Biol. Chem., August 6, 2004; 279(32): 33684 - 33695.
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T. M. Doherty, L. A. Fitzpatrick, D. Inoue, J.-H. Qiao, M. C. Fishbein, R. C. Detrano, P. K. Shah, and T. B. Rajavashisth
Molecular, Endocrine, and Genetic Mechanisms of Arterial Calcification
Endocr. Rev., August 1, 2004; 25(4): 629 - 672.
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Y. Okamatsu, D. Kim, R. Battaglino, H. Sasaki, U. Spate, and P. Stashenko
MIP-1 gamma promotes receptor-activator-of-NF-kappa-B-ligand-induced osteoclast formation and survival.
J. Immunol., August 1, 2004; 173(3): 2084 - 2090.
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M. Bastepe, A. Raas-Rothschild, J. Silver, I. Weissman, S. Wientroub, H. Juppner, and D. Gillis
A Form of Jansen's Metaphyseal Chondrodysplasia with Limited Metabolic and Skeletal Abnormalities Is Caused by a Novel Activating Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Mutation
J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3595 - 3600.
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 Int ImmunolHome page
S. Ishikawa, N. Arase, T. Suenaga, Y. Saita, M. Noda, T. Kuriyama, H. Arase, and T. Saito
Involvement of FcR{gamma} in signal transduction of osteoclast-associated receptor (OSCAR)
Int. Immunol., July 1, 2004; 16(7): 1019 - 1025.
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 Endocr. Rev.Home page
D. Vanderschueren, L. Vandenput, S. Boonen, M. K. Lindberg, R. Bouillon, and C. Ohlsson
Androgens and Bone
Endocr. Rev., June 1, 2004; 25(3): 389 - 425.
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K. Saito, N. Ohara, H. Hotokezaka, S. Fukumoto, K. Yuasa, M. Naito, T. Fujiwara, and K. Nakayama
Infection-induced Up-regulation of the Costimulatory Molecule 4-1BB in Osteoblastic Cells and Its Inhibitory Effect on M-CSF/RANKL-induced in Vitro Osteoclastogenesis
J. Biol. Chem., April 2, 2004; 279(14): 13555 - 13563.
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J. L. Roccisana, N. Kawanabe, H. Kajiya, M. Koide, G. D. Roodman, and S. V. Reddy
Functional Role for Heat Shock Factors in the Transcriptional Regulation of Human RANK Ligand Gene Expression in Stromal/Osteoblast Cells
J. Biol. Chem., March 12, 2004; 279(11): 10500 - 10507.
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N. Okahashi, H. Inaba, I. Nakagawa, T. Yamamura, M. Kuboniwa, K. Nakayama, S. Hamada, and A. Amano
Porphyromonas gingivalis Induces Receptor Activator of NF-{kappa}B Ligand Expression in Osteoblasts through the Activator Protein 1 Pathway
Infect. Immun., March 1, 2004; 72(3): 1706 - 1714.
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 EndocrinologyHome page
H.-I. Shin, P. Divieti, N. A. Sims, T. Kobayashi, D. Miao, A. C. Karaplis, R. Baron, R. Bringhurst, and H. M. Kronenberg
gp130-Mediated Signaling Is Necessary for Normal Osteoblastic Function in Vivo and in Vitro
Endocrinology, March 1, 2004; 145(3): 1376 - 1385.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
A. Matsunuma, T. Kawane, T. Maeda, S. Hamada, and N. Horiuchi
Leptin Corrects Increased Gene Expression of Renal 25-Hydroxyvitamin D3-1{alpha}-Hydroxylase and -24-Hydroxylase in Leptin-Deficient, ob/ob Mice
Endocrinology, March 1, 2004; 145(3): 1367 - 1375.
[Abstract] [Full Text] [PDF]

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K. Suda, N. Udagawa, N. Sato, M. Takami, K. Itoh, J.-T. Woo, N. Takahashi, and K. Nagai
Suppression of Osteoprotegerin Expression by Prostaglandin E2 Is Crucially Involved in Lipopolysaccharide-Induced Osteoclast Formation
J. Immunol., February 15, 2004; 172(4): 2504 - 2510.
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S. Niida, M. Kawahara, Y. Ishizuka, Y. Ikeda, T. Kondo, T. Hibi, Y. Suzuki, K. Ikeda, and N. Taniguchi
{gamma}-Glutamyltranspeptidase Stimulates Receptor Activator of Nuclear Factor-{kappa}B Ligand Expression Independent of Its Enzymatic Activity and Serves as a Pathological Bone-resorbing Factor
J. Biol. Chem., February 13, 2004; 279(7): 5752 - 5756.
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 NEJMHome page
E. Tian, F. Zhan, R. Walker, E. Rasmussen, Y. Ma, B. Barlogie, and J. D. Shaughnessy Jr.
The Role of the Wnt-Signaling Antagonist DKK1 in the Development of Osteolytic Lesions in Multiple Myeloma
N. Engl. J. Med., December 25, 2003; 349(26): 2483 - 2494.
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D.-H. Chung, M. B. Humphrey, M. C. Nakamura, D. G. Ginzinger, W. E. Seaman, and M. R. Daws
CMRF-35-Like Molecule-1, a Novel Mouse Myeloid Receptor, Can Inhibit Osteoclast Formation
J. Immunol., December 15, 2003; 171(12): 6541 - 6548.
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G. Thomas, P. Moffatt, P. Salois, M.-H. Gaumond, R. Gingras, E. Godin, D. Miao, D. Goltzman, and C. Lanctot
Osteocrin, a Novel Bone-specific Secreted Protein That Modulates the Osteoblast Phenotype
J. Biol. Chem., December 12, 2003; 278(50): 50563 - 50571.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
M. Nakamura, N. Udagawa, S. Matsuura, M. Mogi, H. Nakamura, H. Horiuchi, N. Saito, B. Y. Hiraoka, Y. Kobayashi, K. Takaoka, et al.
Osteoprotegerin Regulates Bone Formation through a Coupling Mechanism with Bone Resorption
Endocrinology, December 1, 2003; 144(12): 5441 - 5449.
[Abstract] [Full Text] [PDF]

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A. Takuma, T. Kaneda, T. Sato, S. Ninomiya, M. Kumegawa, and Y. Hakeda
Dexamethasone Enhances Osteoclast Formation Synergistically with Transforming Growth Factor-{beta} by Stimulating the Priming of Osteoclast Progenitors for Differentiation into Osteoclasts
J. Biol. Chem., November 7, 2003; 278(45): 44667 - 44674.
[Abstract] [Full Text] [PDF]

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 J. Appl. Physiol.Home page
E. Seeman
Invited Review: Pathogenesis of osteoporosis
J Appl Physiol, November 1, 2003; 95(5): 2142 - 2151.
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