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The strength and integrity of our bones depends on
maintaining a delicate balance between bone resorption by osteoclasts
andbone formation by osteoblasts. As we age or as a result of disease,this delicate balancing act becomes tipped in favor of osteoclastsso
that bone resorption exceeds bone formation, rendering bonesbrittle
and prone to fracture. A better understanding of the biologyof
osteoclasts and osteoblasts is providing opportunities fordeveloping
therapeutics to treat diseases of bone. Drugs thatinhibit the
formation or activity of osteoclasts are valuablefor treating
osteoporosis, Paget's disease, and inflammation ofbone associated
with rheumatoid arthritis or periodontal disease.Far less attention
has been paid to promoting bone formation with,for example, growth
factors or hormones, an approach that wouldbe a valuable adjunct
therapy for patients receiving inhibitorsof bone resorption.
1 Merck Research Laboratories, West Point, PA
19486, USA.
2 St. Vincent's Institute of Medical
Research, Melbourne 3065, Australia.
*
To whom correspondence should be addressed. E-mail:
gideon_rodan{at}merck.com
Visiting Research Scholar at Lilly Research
Laboratories, Indianapolis, IN 46285, USA.
Inhibition of WNT Signaling by G Protein-Coupled Receptor (GPCR) Kinase 2 (GRK2).
L. Wang, D. Gesty-Palmer, T. A. Fields, and R. F. Spurney (2009)
Mol. Endocrinol.
23, 1455-1465
|Abstract »|Full Text »|PDF »
GM-CSF Regulates Fusion of Mononuclear Osteoclasts into Bone-Resorbing Osteoclasts by Activating the Ras/ERK Pathway.
M. S. Lee, H. S. Kim, J.-T. Yeon, S.-W. Choi, C. H. Chun, H. B. Kwak, and J. Oh (2009)
J. Immunol.
183, 3390-3399
|Abstract »|Full Text »|PDF »
Osteoprotegerin Abrogated Cortical Porosity and Bone Marrow Fibrosis in a Mouse Model of Constitutive Activation of the PTH/PTHrP Receptor.
M. Ohishi, R. Chiusaroli, M. Ominsky, F. Asuncion, C. Thomas, R. Khatri, P. Kostenuik, and E. Schipani (2009)
Am. J. Pathol.
174, 2160-2171
|Abstract »|Full Text »|PDF »
Signal adaptor DAP10 associates with MDL-1 and triggers osteoclastogenesis in cooperation with DAP12.
M. Inui, Y. Kikuchi, N. Aoki, S. Endo, T. Maeda, A. Sugahara-Tobinai, S. Fujimura, A. Nakamura, A. Kumanogoh, M. Colonna, et al. (2009)
PNAS
106, 4816-4821
|Abstract »|Full Text »|PDF »
The Effect of TAK-778 on Gene Expression of Osteoblastic Cells Is Mediated Through Estrogen Receptor.
L. S. Bellesini, M. M. Beloti, G. E. Crippa, K. F. Bombonato-Prado, C. M. Junta, M. M. Marques, G. A. Passos, and A. L. Rosa (2009)
Experimental Biology and Medicine
234, 190-199
|Abstract »|Full Text »|PDF »
Identification of Novel Biphenyl Carboxylic Acid Derivatives as Novel Antiresorptive Agents that Do Not Impair Parathyroid Hormone-Induced Bone Formation.
A. I. Idris, I. R. Greig, E. Bassonga-Landao, S. H. Ralston, and R. J. van 't Hof (2009)
Endocrinology
150, 5-13
|Abstract »|Full Text »|PDF »
Osteoporosis Primer for the Vertebroplasty Practitioner: Expanding the Focus Beyond Needles and Cement.
A.E. Kearns and D.F. Kallmes (2008)
AJNR Am. J. Neuroradiol.
29, 1816-1822
|Abstract »|Full Text »|PDF »
Translational medicine: cancer pain mechanisms and management.
A. Delaney, S. M. Fleetwood-Walker, L. A. Colvin, and M. Fallon (2008)
Br. J. Anaesth.
101, 87-94
|Abstract »|Full Text »|PDF »
Receptor Activator of Nuclear Factor {kappa}B Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease.
A. E. Kearns, S. Khosla, and P. J. Kostenuik (2008)
Endocr. Rev.
29, 155-192
|Abstract »|Full Text »|PDF »
Novel Pro-survival Functions of the Kruppel-like Transcription Factor Egr2 in Promotion of Macrophage Colony-stimulating Factor-mediated Osteoclast Survival Downstream of the MEK/ERK Pathway.
E. W. Bradley, M. M. Ruan, and M. J. Oursler (2008)
J. Biol. Chem.
283, 8055-8064
|Abstract »|Full Text »|PDF »
Wnt/beta-Catenin Signaling Is a Component of Osteoblastic Bone Cell Early Responses to Load-bearing and Requires Estrogen Receptor {alpha}.
V. J. Armstrong, M. Muzylak, A. Sunters, G. Zaman, L. K. Saxon, J. S. Price, and L. E. Lanyon (2007)
J. Biol. Chem.
282, 20715-20727
|Abstract »|Full Text »|PDF »
MITF and PU.1 Recruit p38 MAPK and NFATc1 to Target Genes during Osteoclast Differentiation.
S. M. Sharma, A. Bronisz, R. Hu, K. Patel, K. C. Mansky, S. Sif, and M. C. Ostrowski (2007)
J. Biol. Chem.
282, 15921-15929
|Abstract »|Full Text »|PDF »
Bisphosphonates as Inhibitors of Trypanosoma cruzi Hexokinase: KINETIC AND METABOLIC STUDIES.
C. E. Sanz-Rodriguez, J. L. Concepcion, S. Pekerar, E. Oldfield, and J. A. Urbina (2007)
J. Biol. Chem.
282, 12377-12387
|Abstract »|Full Text »|PDF »
Osteopontin deficiency enhances anabolic action of EP4 agonist at a sub-optimal dose in bone.
N. Kato, K. Kitahara, S. R Rittling, K. Nakashima, D. T Denhardt, H. Kurosawa, Y. Ezura, and M. Noda (2007)
J. Endocrinol.
193, 171-182
|Abstract »|Full Text »|PDF »
Chemokines in Oral Inflammatory Diseases: Apical Periodontitis and Periodontal Disease.
T.A. Silva, G.P. Garlet, S.Y. Fukada, J.S. Silva, and F.Q. Cunha (2007)
Journal of Dental Research
86, 306-319
|Abstract »|Full Text »|PDF »
Inhibin A Is an Endocrine Stimulator of Bone Mass and Strength.
D. S. Perrien, N. S. Akel, P. K. Edwards, A. A. Carver, M. S. Bendre, F. L. Swain, R. A. Skinner, W. R. Hogue, K. M. Nicks, T. M. Pierson, et al. (2007)
Endocrinology
148, 1654-1665
|Abstract »|Full Text »|PDF »
Osteopenia in X-linked hyper-IgM syndrome reveals a regulatory role for CD40 ligand in osteoclastogenesis.
E. Lopez-Granados, S. T. Temmerman, L. Wu, J. C. Reynolds, D. Follmann, S. Liu, D. L. Nelson, F. Rauch, and A. Jain (2007)
PNAS
104, 5056-5061
|Abstract »|Full Text »|PDF »
Attenuation of Bone Mass and Increase of Osteoclast Formation in Decoy Receptor 3 Transgenic Mice.
C.-H. Tang, T.-L. Hsu, W.-W. Lin, M.-Z. Lai, R.-S. Yang, S.-L. Hsieh, and W.-M. Fu (2007)
J. Biol. Chem.
282, 2346-2354
|Abstract »|Full Text »|PDF »
A p38{alpha} Selective Mitogen-Activated Protein Kinase Inhibitor Prevents Periodontal Bone Loss.
K. L. Kirkwood, F. Li, J. E. Rogers, J. Otremba, D. D. Coatney, J. M. Kreider, N. J. D'Silva, S. Chakravarty, S. Dugar, L. S. Higgins, et al. (2007)
J. Pharmacol. Exp. Ther.
320, 56-63
|Abstract »|Full Text »|PDF »
Bone Mineral Density Response to Caloric Restriction-Induced Weight Loss or Exercise-Induced Weight Loss: A Randomized Controlled Trial.
D. T. Villareal, L. Fontana, E. P. Weiss, S. B. Racette, K. Steger-May, K. B. Schechtman, S. Klein, and J. O. Holloszy (2006)
Arch Intern Med
166, 2502-2510
|Abstract »|Full Text »|PDF »
Conjugated linoleic acid inhibits osteoclast differentiation of RAW264.7 cells by modulating RANKL signaling.
M. M. Rahman, A. Bhattacharya, and G. Fernandes (2006)
J. Lipid Res.
47, 1739-1748
|Abstract »|Full Text »|PDF »
Farnesyl Diphosphate Synthase Is a Cytosolic Enzyme in Leishmania major Promastigotes and Its Overexpression Confers Resistance to Risedronate..
A. Ortiz-Gomez, C. Jimenez, A. M. Estevez, J. Carrero-Lerida, L. M. Ruiz-Perez, and D. Gonzalez-Pacanowska (2006)
Eukaryot. Cell
5, 1057-1064
|Abstract »|Full Text »|PDF »
Use of bisphosphonates to improve the durability of total joint replacements..
Wnt signalling in osteoblasts regulates expression of the receptor activator of NF{kappa}B ligand and inhibits osteoclastogenesis in vitro.
G. J. Spencer, J. C. Utting, S. L. Etheridge, T. R. Arnett, and P. G. Genever (2006)
J. Cell Sci.
119, 1283-1296
|Abstract »|Full Text »|PDF »
Reveromycin A, an agent for osteoporosis, inhibits bone resorption by inducing apoptosis specifically in osteoclasts.
J.-T. Woo, M. Kawatani, M. Kato, T. Shinki, T. Yonezawa, N. Kanoh, H. Nakagawa, M. Takami, K. H. Lee, P. H. Stern, et al. (2006)
PNAS
103, 4729-4734
|Abstract »|Full Text »|PDF »
Bone Biology and the Clinical Implications for Osteoporosis.
Acute Neuropathic Joint Disease: A medical emergency?.
A. L. Tan, A. Greenstein, S. J. Jarrett, and D. McGonagle (2005)
Diabetes Care
28, 2962-2964
|Full Text »|PDF »
Osthole-Mediated Cell Differentiation through Bone Morphogenetic Protein-2/p38 and Extracellular Signal-Regulated Kinase 1/2 Pathway in Human Osteoblast Cells.
P.-L. Kuo, Y.-L. Hsu, C.-H. Chang, and J.-K. Chang (2005)
J. Pharmacol. Exp. Ther.
314, 1290-1299
|Abstract »|Full Text »|PDF »
Transcriptional induction of cyclooxygenase-2 in osteoclast precursors is involved in RANKL-induced osteoclastogenesis.
S. Y. Han, N. K. Lee, K. H. Kim, I. W. Jang, M. Yim, J. H. Kim, W. J. Lee, and S. Y. Lee (2005)
Blood
106, 1240-1245
|Abstract »|Full Text »|PDF »
Prostaglandin EP4 receptor agonist augments fixation of hydroxyapatite-coated implants in a rat model of osteoporosis.
K. Hayashi, A. Fotovati, S. A. Ali, K. Oda, H. Oida, and M. Naito (2005)
J Bone Joint Surg Br
87-B, 1150-1156
|Abstract »|Full Text »|PDF »
IL-4 Inhibits Bone-Resorbing Activity of Mature Osteoclasts by Affecting NF-{kappa}B and Ca2+ Signaling.
L. S. Mangashetti, S. M. Khapli, and M. R. Wani (2005)
J. Immunol.
175, 917-925
|Abstract »|Full Text »|PDF »
Sustained Osteomalacia of Long Bones Despite Major Improvement in Other Hypophosphatasia-Related Mineral Deficits in Tissue Nonspecific Alkaline Phosphatase/Nucleotide Pyrophosphatase Phosphodiesterase 1 Double-Deficient Mice.
H. C. Anderson, D. Harmey, N. P. Camacho, R. Garimella, J. B. Sipe, S. Tague, X. Bi, K. Johnson, R. Terkeltaub, and J. L. Millan (2005)
Am. J. Pathol.
166, 1711-1720
|Abstract »|Full Text »|PDF »
Suppressors of Cytokine Signaling-1 and -3 Regulate Osteoclastogenesis in the Presence of Inflammatory Cytokines.
M. Ohishi, Y. Matsumura, D. Aki, R. Mashima, K. Taniguchi, T. Kobayashi, T. Kukita, Y. Iwamoto, and A. Yoshimura (2005)
J. Immunol.
174, 3024-3031
|Abstract »|Full Text »|PDF »
Molecular, Endocrine, and Genetic Mechanisms of Arterial Calcification.
T. M. Doherty, L. A. Fitzpatrick, D. Inoue, J.-H. Qiao, M. C. Fishbein, R. C. Detrano, P. K. Shah, and T. B. Rajavashisth (2004)
Endocr. Rev.
25, 629-672
|Abstract »|Full Text »|PDF »
The Significance of Vasoactive Intestinal Peptide in Immunomodulation.
Curcumin (Diferuloylmethane) Inhibits Receptor Activator of NF-{kappa}B Ligand-Induced NF-{kappa}B Activation in Osteoclast Precursors and Suppresses Osteoclastogenesis.
A. C. Bharti, Y. Takada, and B. B. Aggarwal (2004)
J. Immunol.
172, 5940-5947
|Abstract »|Full Text »|PDF »
Estrogen Deficiency Accelerates Murine Autoimmune Arthritis Associated with Receptor Activator of Nuclear Factor-{kappa}B Ligand-Mediated Osteoclastogenesis.
T. Yoneda, N. Ishimaru, R. Arakaki, M. Kobayashi, T. Izawa, K. Moriyama, and Y. Hayashi (2004)
Endocrinology
145, 2384-2391
|Abstract »|Full Text »|PDF »
Tob deficiency superenhances osteoblastic activity after ovariectomy to block estrogen deficiency-induced osteoporosis.
M. Usui, Y. Yoshida, K. Tsuji, K. Oikawa, K. Miyazono, I. Ishikawa, T. Yamamoto, A. Nifuji, and M. Noda (2004)
PNAS
101, 6653-6658
|Abstract »|Full Text »|PDF »
CMRF-35-Like Molecule-1, a Novel Mouse Myeloid Receptor, Can Inhibit Osteoclast Formation.
D.-H. Chung, M. B. Humphrey, M. C. Nakamura, D. G. Ginzinger, W. E. Seaman, and M. R. Daws (2003)
J. Immunol.
171, 6541-6548
|Abstract »|Full Text »|PDF »
HIV Envelope gp120-mediated Regulation of Osteoclastogenesis via Receptor Activator of Nuclear Factor {kappa}B Ligand (RANKL) Secretion and Its Modulation by Certain HIV Protease Inhibitors through Interferon-{gamma}/RANKL Cross-talk.
Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation.
S. Kim, T. Koga, M. Isobe, B. E. Kern, T. Yokochi, Y. E. Chin, G. Karsenty, T. Taniguchi, and H. Takayanagi (2003)
Genes & Dev.
17, 1979-1991
|Abstract »|Full Text »|PDF »
Lytic Bone Lesions in Human Neuroblastoma Xenograft Involve Osteoclast Recruitment and Are Inhibited by Bisphosphonate.
Y. Sohara, H. Shimada, M. Scadeng, H. Pollack, S. Yamada, W. Ye, C. P. Reynolds, and Y. A. DeClerck (2003)
Cancer Res.
63, 3026-3031
|Abstract »|Full Text »|PDF »
Impaired Osteoclast Formation in Bone Marrow Cultures of Fgf2 Null Mice in Response to Parathyroid Hormone.
Y. Okada, A. Montero, X. Zhang, T. Sobue, J. Lorenzo, T. Doetschman, J. D. Coffin, and M. M. Hurley (2003)
J. Biol. Chem.
278, 21258-21266
|Abstract »|Full Text »|PDF »
Farnesyl Pyrophosphate Synthase Is an Essential Enzyme in Trypanosoma brucei. IN VITRO RNA INTERFERENCE AND IN VIVO INHIBITION STUDIES.
A. Montalvetti, A. Fernandez, J. M. Sanders, S. Ghosh, E. Van Brussel, E. Oldfield, and R. Docampo (2003)
J. Biol. Chem.
278, 17075-17083
|Abstract »|Full Text »|PDF »
Positive Regulation of Endochondral Cartilage Growth by Perichondrial and Periosteal Calcitonin.
Increased Bone Mass Is a Part of the Generalized Lymphoproliferative Disorder Phenotype in the Mouse.
V. Katavic, I. K. Lukic, N. Kovacic, D. Grcevic, J. A. Lorenzo, and A. Marusic (2003)
J. Immunol.
170, 1540-1547
|Abstract »|Full Text »|PDF »
A Randomized Double-Blind Trial to Compare the Efficacy of Teriparatide [Recombinant Human Parathyroid Hormone (1-34)] with Alendronate in Postmenopausal Women with Osteoporosis.
J.-J. Body, G. A. Gaich, W. H. Scheele, P. M. Kulkarni, P. D. Miller, A. Peretz, R. K. Dore, R. Correa-Rotter, A. Papaioannou, D. C. Cumming, et al. (2002)
J. Clin. Endocrinol. Metab.
87, 4528-4535
|Abstract »|Full Text »|PDF »
Abnormal Bone Architecture and Biomechanical Properties with Near-Lifetime Treatment of Rats with PTH.
M. Sato, J. Vahle, A. Schmidt, M. Westmore, S. Smith, E. Rowley, and L. Y. Ma (2002)
Endocrinology
143, 3230-3242
|Abstract »|Full Text »|PDF »
Inhibition of Nanobacteria by Antimicrobial Drugs as Measured by a Modified Microdilution Method.
N. Ciftcioglu, M. A. Miller-Hjelle, J. T. Hjelle, and E. O. Kajander (2002)
Antimicrob. Agents Chemother.
46, 2077-2086
|Abstract »|Full Text »|PDF »
Sequential Treatment with Basic Fibroblast Growth Factor and PTH Is More Efficacious than Treatment with PTH Alone for Increasing Vertebral Bone Mass and Strength in Osteopenic Ovariectomized Rats.
U. T. Iwaniec, Li. Mosekilde, N. G. Mitova-Caneva, J. S. Thomsen, and T. J. Wronski (2002)
Endocrinology
143, 2515-2526
|Abstract »|Full Text »|PDF »
Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation.
K. Yoshida, H. Oida, T. Kobayashi, T. Maruyama, M. Tanaka, T. Katayama, K. Yamaguchi, E. Segi, T. Tsuboyama, M. Matsushita, et al. (2002)
PNAS
99, 4580-4585
|Abstract »|Full Text »|PDF »
Rationale for the role of osteoclast-like cells in arterial calcification.
T. M. DOHERTY, H. UZUI, L. A. FITZPATRICK, P. V. TRIPATHI, C. R. DUNSTAN, K. ASOTRA, and T. B. RAJAVASHISTH (2002)
FASEB J
16, 577-582
|Abstract »|Full Text »|PDF »
ER{alpha} Gene Expression in Human Primary Osteoblasts: Evidence for the Expression of Two Receptor Proteins.
S. Denger, G. Reid, M. Kos, G. Flouriot, D. Parsch, H. Brand, K. S. Korach, V. Sonntag-Buck, and F. Gannon (2001)
Mol. Endocrinol.
15, 2064-2077
|Abstract »|Full Text »|PDF »
Androgens Suppress Osteoclast Formation Induced by RANKL and Macrophage-Colony Stimulating Factor.
D. M. Huber, A. C. Bendixen, P. Pathrose, S. Srivastava, K. M. Dienger, N. K. Shevde, and J. W. Pike (2001)
Endocrinology
142, 3800-3808
|Abstract »|Full Text »|PDF »
Severe Osteopenia in a Young Boy With Kostmann's Congenital Neutropenia Treated With Granulocyte Colony-Stimulating Factor: Suggested Therapeutic Approach.
R. V. Sekhar, S. Culbert, W. K. Hoots, M. J. Klein, H. Zietz, and R. Vassilopoulou-Sellin (2001)
Pediatrics
108, e54-54
|Abstract »|Full Text »|PDF »
Osteoprotegerin Diminishes Advanced Bone Cancer Pain.
N. M. Luger, P. Honore, M. A. C. Sabino, M. J. Schwei, S. D. Rogers, D. B. Mach, D. R. Clohisy, and P. W. Mantyh (2001)
Cancer Res.
61, 4038-4047
|Abstract »|Full Text »
Domain-specific Mutations of a Transforming Growth Factor (TGF)-beta 1 Latency-associated Peptide Cause Camurati-Engelmann Disease Because of the Formation of a Constitutively Active Form of TGF-beta 1.
T. Saito, A. Kinoshita, K.-i. Yoshiura, Y. Makita, K. Wakui, K. Honke, N. Niikawa, and N. Taniguchi (2001)
J. Biol. Chem.
276, 11469-11472
|Abstract »|Full Text »|PDF »
Evaluating the Signal Transduction Mechanism of the Parathyroid Hormone 1 Receptor. EFFECT OF RECEPTOR-G-PROTEIN INTERACTION ON THE LIGAND BINDING MECHANISM AND RECEPTOR CONFORMATION.
S. R. J. Hoare, T. J. Gardella, and T. B. Usdin (2001)
J. Biol. Chem.
276, 7741-7753
|Abstract »|Full Text »|PDF »
Bisphosphonates Are Potent Inhibitors of Trypanosoma cruzi Farnesyl Pyrophosphate Synthase.
A. Montalvetti, B. N. Bailey, M. B. Martin, G. W. Severin, E. Oldfield, and R. Docampo (2001)
J. Biol. Chem.
276, 33930-33937
|Abstract »|Full Text »|PDF »
Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation.
K. Yoshida, H. Oida, T. Kobayashi, T. Maruyama, M. Tanaka, T. Katayama, K. Yamaguchi, E. Segi, T. Tsuboyama, M. Matsushita, et al. (2002)
PNAS
99, 4580-4585
|Abstract »|Full Text »|PDF »
