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Persistent bone-sparing effect of interleukin-1 receptor antagonist: A hypothesis on the role of IL-1 in ovariectomy-induced bone loss

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Abstract

The recent finding that treatment with the interleukin-1 (IL-1) inhibitor, interleukin-1 receptor antagonist (IL-1ra) decreases bone loss and bone resorption in ovariectomized rats, strongly suggested that IL-1 mediates, at least in part, the effects of estrogen deficiency on bone resorption. Although in vitro studies have shown that IL-1 activates mature osteoclasts and stimulates osteoclastogenesis, the two main mechanisms by which estrogen deficiency stimulates bone resorption, it is still unclear whether IL-1 mediates both effects of estrogen deficiency in vivo. To investigate this matter, we have examined the changes in bone mineral density (BMD) which occur in ovariectomized rats after completion of 1 month of estrogen or IL-1ra treatment begun at the time of ovariectomy. Ovariectomy caused a marked decreased in BMD which was blocked by 17β estradiol and decreased by IL-1ra. Cessation of estrogen therapy was followed by a rapid induction of bone loss, indicating that estrogen blocks the activation and utilization of mature osteoclasts without depleting the bone microenvironment of osteoclast precursors and mature, inactive osteoclasts. In contrast, ovariectomized rats treated with IL-1ra maintained a stable bone density for the first 4 weeks after completion of the treatment. In these rats, bone loss resumed not earlier than 6 weeks after discontinuation of the IL-1ra treatment. Estrogen deficiency was necessary to unveil the bone-sparing effect of IL-1ra because in a control experiment in which rats were treated with IL-1ra for the 4 weeks before ovariectomy, BMD began to decrease immediately after ovariectomy. Based on these results we propose the hypothesis that in conditions of estrogen deficiency, the main effect of IL-1ra is to block the proliferation and differentiation of osteoclast precursors, an event that results in the depletion of mature, rapidly responsive osteoclasts. We also suggest that estrogen may have important direct effects on the regulation of osteoclast activity.

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References

  1. Selby PL, Peacock M, Barkworth SA, Brown WB, Taylor GA (1985) Early effects of ethinyloestradiol and norethisterone treatment in post-menopausal women on bone resorption and calcium-regulating hormones. Clin Sci 69:265–271

    Google Scholar 

  2. Ettinger B, Genant HK, Cann EC (1985) Long-term estrogen replacement therapy prevents bone loss and fractures. Ann Intern Med 102:319–324

    Google Scholar 

  3. Lindsay R, Hart DM, Forrest C, Baird C (1980) Prevention of spinal osteoporosis in oophorectomized women. Lancet 2:1151–1154

    Google Scholar 

  4. Oursler MJ, Osdoby P, Pyfferoen J, Riggs BL, Spelsberg TC (1991) Avian osteoclasts as estrogen target cells. Proc Natl Acad Sci USA 88:6613–6617

    Google Scholar 

  5. Jilka RL, Hangoc G, Girasole G, Passeri G, Williams DC, Abrams JS, Boyce B, Broxmeyer H, Manolagas SC (1992) Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science 257:88–91

    Google Scholar 

  6. Raisz LG (1988) Local and systemic factors in the pathogenesis of osteoporosis. N Engl J Med 318:818–828

    Google Scholar 

  7. Horowitz M (1993) Cytokines and estrogen in bone: antiosteoporotic effects. Science 260:626–627

    Google Scholar 

  8. Dinarello CA (1991) Interleukin-1 and interleukin-1 antagonism. Blood 777:1627–1652

    Google Scholar 

  9. Smith KA, Lachman LB, Oppenheim JJ, Favata MF (1980) The functional relationships of the interleukins. J Exp Med 151: 1551–1556

    Google Scholar 

  10. Dinarello CA (1984) Interleukin-1. Revs Infect Dis 6:51–95

    Google Scholar 

  11. Gowen M, Wood DD, Ihrie EJ, McGuire MKB, Russell RGG (1983) An interleukin-1-like factor stimulates bone resorption in vitro. Nature 306:378–380

    Google Scholar 

  12. Lorenzo JA, Sousa SL, Alander C, Raisz LG, Dinarello CA (1987) Comparison of the bone-resorbing activity in the supernatants from phytohemaglutinin-stimulating human peripheral blood mononuclear cells with that of cytokines through the use of an antiserum to interleukin 1. Endocrinology 121:1164–1170

    Google Scholar 

  13. Boyce BF, Aufdemorte TB, Garrett IR, Yates AJP, Mundy GR (1989) Effects of interleukin-1 on bone turnover in normal mice. Endocrinology 125:1142–1150

    Google Scholar 

  14. Konig A, Muhlbauer RC, Fleisch H (1988) Tumor necrosis factor α and interleukin-1 stimulate bone resorption in vivo as measured by urinary (3H) tetracycline excretion from prelabeled mice. J Bone Miner Res 3:621–627

    Google Scholar 

  15. Sabatini M, Boyce B, Aufdemorte T, Bonewald L, Mundy GR (1988) Infusions of recombinant human interleukin 1 alpha and beta cause hypercalcemia in normal mice. Proc Natl Acad Sci USA 85:5235–5239

    Google Scholar 

  16. Hannum CH, Wilcox CJ, Arend WP, Joslin FG, Dripps DJ, Heimdal PL, Armes LG, Sommer A, Eisenberg SP, Thompson RC (1990) Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343:336–340

    Google Scholar 

  17. Carter DB, Deibel Jr MR, Dunn CJ, Tomich C-SC, Laborde AL, Slighton JL, Berger AE, Bienkowski MJ, Sun FF, McEwan RN, Harris PKW, Yem AW, Waszak GA, Chosay JG, Sieu LC, Hardee MM, Zurcher-Neely HA, Reardon IM, Heinrikson RL, Truesdell SE, Shelly JA, Eessalu TE, Taylor BM, Tracey DE (1990) Purification, cloning, expression and biological characterization of an interleukin-1 receptor antagonist protein. Nature 344:633–638

    Google Scholar 

  18. Arend WP, Joslin FG, Thompson RC, Hannum CH (1989) An IL-1 inhibitor from human monocytes. J Immunol 143:1851–1858

    Google Scholar 

  19. Arend WP (1991) Interleukin 1 receptor antagonist: a new member of the interleukin 1 family. J Clin Invest 88:1445–1451

    Google Scholar 

  20. Kimble RB, Vannice JL, Bloedow DC, Thompson RC, Hopfer W, Kung V, Brownfield C, Pacifici R. (1994) Interleukin-1 receptor antagonist decreases bone loss and bone resorption in ovariectomized rats. J Clin Invest 93:1959–1967

    Google Scholar 

  21. Gowen M, Mundy GR (1986) Actions of interleukin-1, interleukin-2, and interferon γ on bone resorption in vitro. J Immunol 136:2478–2482

    Google Scholar 

  22. Pfeilschifter J, Chenu C, Bird A, Mundy GR, Roodman GD (1989) Interleukin-1 and tumor necrosis factor stimulate the for-mation of human osteoclast-like cells in vitro. J Bone Miner Res 4:113–118

    Google Scholar 

  23. Griffin MG, Kimble R, Hopfer W, Pacifici R (1993) Dual energy x-ray absorptiometry (DEXA) of the rat: accuracy, precision and measurement of bone loss. J Bone Miner Res 8:795–800

    Google Scholar 

  24. Takahashi N, Yamana H, Yoshiki S, Roodman GD, Mundy GR, Jones SJ, Boyde A, Suda T (1988) Osteoclast-like cell formation and its regulation by osteotropic hormones in mouse bone marrow cultures. Endocrinology 122:1373–1382

    Google Scholar 

  25. Takahashi N, Akatsu T, Sasaki T, Nicholson GC, Moseley JM, Martin TJ, Suda T (1988) Induction of calcitonin receptors by 1α, 25-dihydroxyvitamin D3 in osteoclast-like multinucleated cells formed from mouse bone marrow cells. Endocrinology 123:1504–1510

    Google Scholar 

  26. Amman P, Rizzoli R, Slosman D, Bonjour JP (1992) Sequential and precise in vivo measurements of bone mineral density in rats using dual energy X-ray absorptiometry. J Bone Miner Res 7:311–316

    Google Scholar 

  27. Lindsay R (1988) Sex steroids in the pathogenesis and prevention of osteoporosis. In: Riggs BL, Melton LJ (eds) Osteoporosis. Raven Press, New York, pp 333–358

    Google Scholar 

  28. Wronski TJ, Dann LM, Qi H, Yen CF (1993) Skeletal effects of withdrawal of estrogen and diphosphonate treatment in ovariectomized rats. Calcif Tissue Int 53:210–216

    Google Scholar 

  29. Kimble RB, Matayoshi AB, Vannice JL, Pacifici R (in press) Long-term treatment with IL-1 receptor antagonist (IL-1ra) blocks bone loss in ovariectomized rats (abstract). J Bone Miner Res

  30. Horsman A, Jones M, Francis R, Nordin BEC (1983) The effect of estrogen dose on postmenopausal bone loss. N Engl J Med 309:1405–1407

    Google Scholar 

  31. Wronski TJ, Cintron M, Doherty AL, Dann LM (1988) Estrogen treatment prevents osteopenia and depresses bone turnover in ovariectomized rats. Endocrinology 123:681–686

    Google Scholar 

  32. Kalu DN, Liu CC, Salerno E, Hollis B, Echon R, Ray M (1991) Skeletal response of ovariectomized rats to low and high doses of 17β-estradiol. Bone Miner 14:175–187

    Google Scholar 

  33. Chow J, Tobias JH, Colston KW, Chambers TJ (1992) Estrogen maintains trabecular bone volume in rats not only by suppression of bone resorption but also by stimulation of bone formation. J Clin Invest 89:74–78

    Google Scholar 

  34. Bain ST, Bailey SC, Celino DL, Lantry MM, Edwards MW (1993) High-dose estrogen inhibits bone resorption and stimulates bone formation in the ovariectomized mouse. J Bone Miner Res 8:435–442

    Google Scholar 

  35. Suda T, Takahashi N, Martin TJ (1992) Modulation of osteoclast differentiation. Endocrinol Rev 13:66–80

    Google Scholar 

  36. Thomson BM, Saklatvala J, Chambers TJ (1986) Osteoblasts mediate interleukin 1 stimulation of bone resorption by rat osteoclasts. J Exp Med 164:104–112

    Google Scholar 

  37. Parfitt AM (1988) Bone remodeling: relationship to the amount and structure of bone, and the pathogenesis and prevention of fractures. In: Riggs BL (ed) Osteoporosis. Raven Press, New York, pp 45–93

    Google Scholar 

  38. Oursler MJ, Pederson L, Pyfferoen J, Osdoby P, Fitzpatrick L, Spelsberg TC (1993) Estrogen modulation of avian osteoclast lysosomal gene expression. Endocrinology 132:1373–1380

    Google Scholar 

  39. Thomson BM, Mundy GR, Chambers TJ (1987) Tumor necrosis factor α and β induce osteoblastic cells to stimulate osteoclastic bone resorption. J Immunol 138:775–779

    Google Scholar 

  40. Baron R, Vignery A, Horowitz M (1984) Lymphocytes, macrophages and the regulation of bone remodeling. In Peck W (ed) Bone & mineral research 2. Elsevier, Amsterdam, pp 175–245

    Google Scholar 

  41. Delmas PD (1988) Biochemical markers of bone turnover in osteoporosis. In: Riggs BL, Melton LJ (eds) Osteoporosis. Raven Press, New York, pp 297–316

    Google Scholar 

  42. Choen-Solal ME, Graulet AM, Denne MA, Gueris J, Baylink D, de Vernejoul MC (1993) Peripheral monocyte culture supernatants of menopausal women can induce bone resorption: involvement of cytokines. J Clin Endocrinol Metab 77:1648–1653

    Google Scholar 

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Authors and Affiliations

  1. Division of Bone and Mineral Diseases, Washington University School of Medicine and The Jewish Hospital of St. Louis, 216 S. Kingshighway, St. Louis, Missouri, USA

    R. B. Kimble, R. Kitazawa & R. Pacifici

  2. Synergen Inc., Boulder, Colorado, USA

    J. L. Vannice

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  1. R. B. Kimble
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  2. R. Kitazawa
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  3. J. L. Vannice
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  4. R. Pacifici
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Kimble, R.B., Kitazawa, R., Vannice, J.L. et al. Persistent bone-sparing effect of interleukin-1 receptor antagonist: A hypothesis on the role of IL-1 in ovariectomy-induced bone loss. Calcif Tissue Int 55, 260–265 (1994). https://doi.org/10.1007/BF00310403

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  • DOI: https://doi.org/10.1007/BF00310403

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