Abstract
To evaluate the role of tumor necrosis factor (TNF alpha) in bone loss resulting from estrogen deficiency, the effects of ovariectomy were explored in six-month-old transgenic mice expressing high blood levels of a soluble TNF receptor type I (sTNFR1)-FcIgG3 fusion protein, which neutralizes TNF alpha, and in their nontransgenic littermates used as controls. These transgenic mice were identical to control mice in bone mass (evaluated by bone mineral density and content) and strength. 12 weeks after ovariectomy, the decrease in bone mass and increase in osteocalcin (marker of bone turnover) found in control mice were not observed in transgenic mice, which were not different from sham-operated mice, transgenic or not. This observation suggests a critical role for TNF alpha in the pathogenesis of bone loss induced by estrogen deficiency, a common cause of morbidity in postmenopausal women.
Full Text
The Full Text of this article is available as a PDF (146.2 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Ammann P., Rizzoli R., Meyer J. M., Bonjour J. P. Bone density and shape as determinants of bone strength in IGF-I and/or pamidronate-treated ovariectomized rats. Osteoporos Int. 1996;6(3):219–227. doi: 10.1007/BF01622738. [DOI] [PubMed] [Google Scholar]
- Ammann P., Rizzoli R., Slosman D., Bonjour J. P. Sequential and precise in vivo measurement of bone mineral density in rats using dual-energy x-ray absorptiometry. J Bone Miner Res. 1992 Mar;7(3):311–316. doi: 10.1002/jbmr.5650070310. [DOI] [PubMed] [Google Scholar]
- Bertolini D. R., Nedwin G. E., Bringman T. S., Smith D. D., Mundy G. R. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature. 1986 Feb 6;319(6053):516–518. doi: 10.1038/319516a0. [DOI] [PubMed] [Google Scholar]
- Black K., Garrett I. R., Mundy G. R. Chinese hamster ovarian cells transfected with the murine interleukin-6 gene cause hypercalcemia as well as cachexia, leukocytosis and thrombocytosis in tumor-bearing nude mice. Endocrinology. 1991 May;128(5):2657–2659. doi: 10.1210/endo-128-5-2657. [DOI] [PubMed] [Google Scholar]
- Bourrin S., Palle S., Pupier R., Vico L., Alexandre C. Effect of physical training on bone adaptation in three zones of the rat tibia. J Bone Miner Res. 1995 Nov;10(11):1745–1752. doi: 10.1002/jbmr.5650101118. [DOI] [PubMed] [Google Scholar]
- Chaudhary L. R., Spelsberg T. C., Riggs B. L. Production of various cytokines by normal human osteoblast-like cells in response to interleukin-1 beta and tumor necrosis factor-alpha: lack of regulation by 17 beta-estradiol. Endocrinology. 1992 May;130(5):2528–2534. doi: 10.1210/endo.130.5.1572280. [DOI] [PubMed] [Google Scholar]
- Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med. 1993 Jun;94(6):646–650. doi: 10.1016/0002-9343(93)90218-e. [DOI] [PubMed] [Google Scholar]
- Felix R., Cecchini M. G., Fleisch H. Macrophage colony stimulating factor restores in vivo bone resorption in the op/op osteopetrotic mouse. Endocrinology. 1990 Nov;127(5):2592–2594. doi: 10.1210/endo-127-5-2592. [DOI] [PubMed] [Google Scholar]
- Felix R., Cecchini M. G., Hofstetter W., Guenther H. L., Fleisch H. Production of granulocyte-macrophage (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) by rat clonal osteoblastic cell population CRP 10/30 and the immortalized cell line IRC10/30-myc1 stimulated by tumor necrosis factor alpha. Endocrinology. 1991 Feb;128(2):661–667. doi: 10.1210/endo-128-2-661. [DOI] [PubMed] [Google Scholar]
- Garcia I., Miyazaki Y., Araki K., Araki M., Lucas R., Grau G. E., Milon G., Belkaid Y., Montixi C., Lesslauer W. Transgenic mice expressing high levels of soluble TNF-R1 fusion protein are protected from lethal septic shock and cerebral malaria, and are highly sensitive to Listeria monocytogenes and Leishmania major infections. Eur J Immunol. 1995 Aug;25(8):2401–2407. doi: 10.1002/eji.1830250841. [DOI] [PubMed] [Google Scholar]
- Girasole G., Jilka R. L., Passeri G., Boswell S., Boder G., Williams D. C., Manolagas S. C. 17 beta-estradiol inhibits interleukin-6 production by bone marrow-derived stromal cells and osteoblasts in vitro: a potential mechanism for the antiosteoporotic effect of estrogens. J Clin Invest. 1992 Mar;89(3):883–891. doi: 10.1172/JCI115668. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Horowitz M. C. Cytokines and estrogen in bone: anti-osteoporotic effects. Science. 1993 Apr 30;260(5108):626–627. doi: 10.1126/science.8480174. [DOI] [PubMed] [Google Scholar]
- Jilka R. L., Hangoc G., Girasole G., Passeri G., Williams D. C., Abrams J. S., Boyce B., Broxmeyer H., Manolagas S. C. Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science. 1992 Jul 3;257(5066):88–91. doi: 10.1126/science.1621100. [DOI] [PubMed] [Google Scholar]
- Johnson R. A., Boyce B. F., Mundy G. R., Roodman G. D. Tumors producing human tumor necrosis factor induced hypercalcemia and osteoclastic bone resorption in nude mice. Endocrinology. 1989 Mar;124(3):1424–1427. doi: 10.1210/endo-124-3-1424. [DOI] [PubMed] [Google Scholar]
- Kalu D. N. The ovariectomized rat model of postmenopausal bone loss. Bone Miner. 1991 Dec;15(3):175–191. doi: 10.1016/0169-6009(91)90124-i. [DOI] [PubMed] [Google Scholar]
- Kimble R. B., Matayoshi A. B., Vannice J. L., Kung V. T., Williams C., Pacifici R. Simultaneous block of interleukin-1 and tumor necrosis factor is required to completely prevent bone loss in the early postovariectomy period. Endocrinology. 1995 Jul;136(7):3054–3061. doi: 10.1210/endo.136.7.7789332. [DOI] [PubMed] [Google Scholar]
- Kimble R. B., Vannice J. L., Bloedow D. C., Thompson R. C., Hopfer W., Kung V. T., Brownfield C., Pacifici R. Interleukin-1 receptor antagonist decreases bone loss and bone resorption in ovariectomized rats. J Clin Invest. 1994 May;93(5):1959–1967. doi: 10.1172/JCI117187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kitazawa R., Kimble R. B., Vannice J. L., Kung V. T., Pacifici R. Interleukin-1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice. J Clin Invest. 1994 Dec;94(6):2397–2406. doi: 10.1172/JCI117606. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Konchalovskaia N. M., Popova T. B., Bialko N. K. Sovremennoe sostoianie problemy toksicheskogo gepatita. Gig Tr Prof Zabol. 1974 Dec;0(12):10–13. [PubMed] [Google Scholar]
- Manolagas S. C., Jilka R. L. Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N Engl J Med. 1995 Feb 2;332(5):305–311. doi: 10.1056/NEJM199502023320506. [DOI] [PubMed] [Google Scholar]
- Miller S. C., Wronski T. J. Long-term osteopenic changes in cancellous bone structure in ovariectomized rats. Anat Rec. 1993 Jul;236(3):433–441. doi: 10.1002/ar.1092360303. [DOI] [PubMed] [Google Scholar]
- Pacifici R., Brown C., Puscheck E., Friedrich E., Slatopolsky E., Maggio D., McCracken R., Avioli L. V. Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5134–5138. doi: 10.1073/pnas.88.12.5134. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pacifici R., Rifas L., McCracken R., Vered I., McMurtry C., Avioli L. V., Peck W. A. Ovarian steroid treatment blocks a postmenopausal increase in blood monocyte interleukin 1 release. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2398–2402. doi: 10.1073/pnas.86.7.2398. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pacifici R., Vannice J. L., Rifas L., Kimble R. B. Monocytic secretion of interleukin-1 receptor antagonist in normal and osteoporotic women: effects of menopause and estrogen/progesterone therapy. J Clin Endocrinol Metab. 1993 Nov;77(5):1135–1141. doi: 10.1210/jcem.77.5.8077304. [DOI] [PubMed] [Google Scholar]
- Parfitt A. M., Drezner M. K., Glorieux F. H., Kanis J. A., Malluche H., Meunier P. J., Ott S. M., Recker R. R. Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 1987 Dec;2(6):595–610. doi: 10.1002/jbmr.5650020617. [DOI] [PubMed] [Google Scholar]
- Parfitt A. M. Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone. J Cell Biochem. 1994 Jul;55(3):273–286. doi: 10.1002/jcb.240550303. [DOI] [PubMed] [Google Scholar]
- Poli V., Balena R., Fattori E., Markatos A., Yamamoto M., Tanaka H., Ciliberto G., Rodan G. A., Costantini F. Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO J. 1994 Mar 1;13(5):1189–1196. doi: 10.1002/j.1460-2075.1994.tb06368.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Riggs B. L., Melton L. J., 3rd Involutional osteoporosis. N Engl J Med. 1986 Jun 26;314(26):1676–1686. doi: 10.1056/NEJM198606263142605. [DOI] [PubMed] [Google Scholar]
- Udagawa N., Takahashi N., Katagiri T., Tamura T., Wada S., Findlay D. M., Martin T. J., Hirota H., Taga T., Kishimoto T. Interleukin (IL)-6 induction of osteoclast differentiation depends on IL-6 receptors expressed on osteoblastic cells but not on osteoclast progenitors. J Exp Med. 1995 Nov 1;182(5):1461–1468. doi: 10.1084/jem.182.5.1461. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vassalli P. The pathophysiology of tumor necrosis factors. Annu Rev Immunol. 1992;10:411–452. doi: 10.1146/annurev.iy.10.040192.002211. [DOI] [PubMed] [Google Scholar]
- Yamada H., Iwase S., Mohri M., Kufe D. Involvement of a nuclear factor-kappa B-like protein in induction of the macrophage colony-stimulating factor gene by tumor necrosis factor. Blood. 1991 Oct 15;78(8):1988–1995. [PubMed] [Google Scholar]