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V. A. Connecticut Healthcare System, Newington, Connecticut 06111; and The University of Connecticut Health Center, Farmington, Connecticut 06030
Address all correspondence and requests for reprints to: Dr. Sun-Kyeong Lee, Division of Endocrinology, Department of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut 06030-1850.
We studied the effects of PTH on the expression of tumor necrosis
factor-related activation-induced cytokine (TRANCE), osteoprotegerin
(OPG), and receptor activator of NF 
B (RANK) messenger RNA
(mRNA) in cultured murine bone marrow, calvaria, and osteoblasts.
TRANCE, OPG, and RANK are recently identified regulators of osteoclast
formation. Bone marrow cells were cultured with or without PTH(1–34)
for 6 days. TRANCE, OPG, and RANK mRNA were measured by RT-PCR. In
6-day cultures, PTH stimulated the number of OCL/well in a
dose-dependent manner. A time course showed significant
(P < 0.01) increases in OCL/well after 24 h
of PTH (100 ng/ml). TRANCE mRNA expression, like OCL formation,
increased dose dependently and was maximal, with 10–100 ng/ml PTH. In
contrast, OPG mRNA expression was decreased by 0.1 ng/ml PTH (40%) and
completely abolished by 1 ng/ml. TRANCE mRNA expression was rapidly
stimulated by PTH (maximal response at 1 h, 8.1-fold over
control). Expression declined by 40% at 24 h but was still much
greater than control at 6 days (4.6-fold) in a time-course study. PTH
caused a transient stimulation of OPG mRNA at 1 h (2-fold), which
returned to basal levels by 2 h. After 6 h, PTH completely
inhibited OPG mRNA. There were only minor effects of PTH on RANK mRNA
expression. PTH had less potent effects on TRANCE and OPG mRNA
expression in calvaria organ cultures and osteoblasts. In mouse
calvaria cultures, TRANCE expression was detectable in controls and was
increased 2.9-fold by PTH at 24 h. PTH treatment of calvaria
decreased OPG expression by 30% at 6 h. MC3T3 E-1 osteoblastic
cells expressed minimal levels of TRANCE mRNA either before or after
PTH treatment. OPG mRNA was present in MC3T3 E-1 cells, but levels were
not modulated by PTH. In primary osteoblastic cells, PTH stimulated
TRANCE mRNA expression 4-fold at 2 h and inhibited OPG mRNA
expression by 46%.
These results demonstrate a tight correlation between the ability of
PTH to stimulate OCL formation in marrow culture and expression of
TRANCE (r = 0.87, P 
0.05) and OPG mRNA (r=
-0.88, P 0.05). Reciprocal regulation of TRANCE
and OPG mRNA by PTH preceded its effects on OCL formation by 18–23 h.
Hence, it is likely that PTH regulates bone resorption, at least in
part, via its effects on TRANCE and OPG expression.
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S.-K. Lee, J. Kalinowski, S. Jastrzebski, and J. A. Lorenzo 1,25 (OH)2 Vitamin D3-Stimulated Osteoclast Formation in Spleen-Osteoblast Cocultures Is Mediated in Part by Enhanced IL-1{alpha} and Receptor Activator of NF-{kappa}B Ligand Production in Osteoblasts J. Immunol., September 1, 2002; 169(5): 2374 - 2380. [Abstract] [Full Text] [PDF]
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 Y. Jiang, C. K. Mehta, T.-Y. Hsu, and F. F. H. Alsulaimani Bacteria Induce Osteoclastogenesis via an Osteoblast-Independent Pathway Infect. Immun., June 1, 2002; 70(6): 3143 - 3148. [Abstract] [Full Text] [PDF]
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G. Coen, P. Ballanti, A. Balducci, S. Calabria, M. S. Fischer, L. Jankovic, M. Manni, M. Morosetti, E. Moscaritolo, D. Sardella, et al. Serum osteoprotegerin and renal osteodystrophy Nephrol. Dial. Transplant., February 1, 2002; 17(2): 233 - 238. [Abstract] [Full Text] [PDF]
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S. Khosla Minireview: The OPG/RANKL/RANK System Endocrinology, December 1, 2001; 142(12): 5050 - 5055. [Abstract] [Full Text] [PDF]
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 U Feige Osteoprotegerin Ann Rheum Dis, November 1, 2001; 60(90003): iii81 - 84. [Full Text] [PDF]
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P. J. Kostenuik, C. Capparelli, S. Morony, S. Adamu, G. Shimamoto, V. Shen, D. L. Lacey, and C. R. Dunstan OPG and PTH-(1-34) Have Additive Effects on Bone Density and Mechanical Strength in Osteopenic Ovariectomized Rats Endocrinology, October 1, 2001; 142(10): 4295 - 4304. [Abstract] [Full Text] [PDF]
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R. Gopalakrishnan, H. Ouyang, M. J. Somerman, L. K. McCauley, and R. T. Franceschi Matrix {gamma}-Carboxyglutamic Acid Protein Is a Key Regulator of PTH-Mediated Inhibition of Mineralization in MC3T3-E1 Osteoblast-Like Cells Endocrinology, October 1, 2001; 142(10): 4379 - 4388. [Abstract] [Full Text] [PDF]
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 B. A. Watkins, Y. Li, and M. F. Seifert Nutraceutical Fatty Acids as Biochemical and Molecular Modulators of Skeletal Biology J. Am. Coll. Nutr., October 1, 2001; 20(90005): 410S - 416. [Abstract] [Full Text]
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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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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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 B. A. Watkins, Y. Li, H. E. Lippman, and M. F. Seifert Omega-3 Polyunsaturated Fatty Acids and Skeletal Health Experimental Biology and Medicine, June 1, 2001; 226(6): 485 - 497. [Abstract] [Full Text] [PDF]
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B. Z. Leder, M. R. Smith, M. A. Fallon, M.-L. T. Lee, and J. S. Finkelstein Effects of Gonadal Steroid Suppression on Skeletal Sensitivity to Parathyroid Hormone in Men J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 511 - 516. [Abstract] [Full Text]
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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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D. Grcevic, S.-K. Lee, A. Marusic, and J. A. Lorenzo Depletion of CD4 and CD8 T Lymphocytes in Mice In Vivo Enhances 1,25-Dihydroxyvitamin D3-Stimulated Osteoclast-Like Cell Formation In Vitro by a Mechanism That Is Dependent on Prostaglandin Synthesis J. Immunol., October 15, 2000; 165(8): 4231 - 4238. [Abstract] [Full Text] [PDF]
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 S. L. Teitelbaum Bone Resorption by Osteoclasts Science, September 1, 2000; 289(5484): 1504 - 1508. [Abstract] [Full Text]
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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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X. Li, Y. Okada, C. C. Pilbeam, J. A. Lorenzo, C. R. J. Kennedy, R. M. Breyer, and L. G. Raisz Knockout of the Murine Prostaglandin EP2 Receptor Impairs Osteoclastogenesis in Vitro Endocrinology, June 1, 2000; 141(6): 2054 - 2061. [Abstract] [Full Text] [PDF]
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 C. Capparelli, P. J. Kostenuik, S. Morony, C. Starnes, B. Weimann, G. Van, S. Scully, M. Qi, D. L. Lacey, and C. R. Dunstan Osteoprotegerin Prevents and Reverses Hypercalcemia in a Murine Model of Humoral Hypercalcemia of Malignancy Cancer Res., February 1, 2000; 60(4): 783 - 787. [Abstract] [Full Text]
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P. Collin-Osdoby, L. Rothe, F. Anderson, M. Nelson, W. Maloney, and P. Osdoby Receptor Activator of NF-kappa B and Osteoprotegerin Expression by Human Microvascular Endothelial Cells, Regulation by Inflammatory Cytokines, and Role in Human Osteoclastogenesis J. Biol. Chem., June 1, 2001; 276(23): 20659 - 20672. [Abstract] [Full Text] [PDF]
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