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Genetic Determinants of IL-6 Expression Levels Do Not Influence Bone Loss in Inflammatory Bowel Disease

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Abstract

Bone loss in inflammatory bowel disease (IBD) is presumed to be mediated by inflammation. Increased levels of the multifunctional cytokine IL-6 in inflammatory diseases have been proposed to be the link in such “inflammation-mediated osteopenia.” A recently described G/C polymorphism with an effect on transcription rate and plasma levels of IL-6 suggests a genetically determined difference in the degree of the IL-6 response to stressful stimuli between individuals. This study aimed to assess the frequency of genotypes and haplotypes of the G/C polymorphism of IL-6 in IBD patients. A further aim was to assess whether carriage of the potentially protective CC genotype is favorable with respect to the development of bone disease in IBD. The IL-6 polymorphism was typed in 105 IBD patients and 113 healthy controls. Bone mineral density was evaluated at baseline and after a prospective 2-year-follow-up. The favorable CC genotype with decreased IL-6 release was not underrepresented in IBD patients compared to healthy controls. Carriage of this genotype was not protective with respect to the development of bone disease, either for the bone mineral density at baseline or for the prospectively observed bone loss. Within the subgroup of patients who did not receive steroids during follow-up, the prospectively observed bone loss was even slightly higher in CC carriers, but differences did not reach significance. Genetically determined differences in the degree of the IL-6 response to stressful stimuli are no major predictors for the degree of bone disease in IBD patients.

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REFERENCES

  1. Fishman D, Faulds G, Jeffry R, Mohamed-Ali V, Yudkin JS, Humphries S, et al: The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile arthritis. J Clin Invest 102:1369–1276, 1998

    Google Scholar 

  2. Fernandez-Real JM, Broch M, Vendrell J, Gutierrez C, Casamitjana R, Pugeat M, et al: Interleukin-6 gene polymorphism and insulin sensitivity. Diabetes 49:517–520, 2000

    Google Scholar 

  3. Fernandez-Real JM, Broch M, Vendrell J, Richart C, Ricart W: Interleukin-6 gene polymorphism and lipid abnormalities in healthy subjects. J Clin Endocrinol Metab 85:1334–13349, 2000

    Google Scholar 

  4. Valentine JF, Sninsky CA: Prevention and treatment of osteoporosis in patients with inflammatory bowel disease. Am J Gastroenterol 94:878–883, 1999

    Google Scholar 

  5. Compston JE: Review article: Osteoporosis, corticosteroids and inflammatory bowel disease. Aliment Pharmacol Ther 9:237–250, 1995

    Google Scholar 

  6. Silvennoinen JA, Karttunen TJ, Niemelä SE, Manelius JJ, Lehtola JK: A controlled study of bone mineral density in patients with inflammatory bowel disease. Gut 37:71–76, 1995

    Google Scholar 

  7. Schulte C, Dignass AU, Mann K, Goebell H: Reduced bone mineral density and unbalanced bone metabolism in patients with inflammatory bowel disease. Inflamm Bowel Dis 4(4):268–275, 1998

    Google Scholar 

  8. Schulte C, Dignass AU, Mann K, Goebell H: Bone loss in patients with inflammatory bowel disease is less than expected: A follow-up study. Scand J Gastroenterol 34:696–702, 1999

    Google Scholar 

  9. Abitbol V, Roux C, Chaussade S, Guillemant S, Kolta S, Dougados M, et al: Metabolic bone assessment in patients with inflammatory bowel disease. Gastroenterology 108:417–422, 1995

    Google Scholar 

  10. Bischoff SC, Herrmann A, Göke M, Manns MP, von zur Mühlen A, Brabant G: Altered bone metabolism in inflammatory bowel disease. Am J Gastroenterol 92:1157–1163, 1997

    Google Scholar 

  11. Sartor RB: Pathogenesis and immune mechanisms of chronic inflammatory bowel diseases. Am J Gastroenterol 92:5S–11S, 1997

    Google Scholar 

  12. Minne HW, Pfeilschifter J, Scharla S, Mutschelknauss S, Schwarz A, Krempien B, et al: Inflammation mediated osteopenia in the rat: A new animal model for pathological loss of bone mass. Endocrinology 115:50–54, 1984

    Google Scholar 

  13. Roodman GD: Roles of cytokines in the regulation of bone resorption. Calcif Tissue Int 53:S94–S98, 1993

    Google Scholar 

  14. Manolagas SC, Jilka RL: Bone marrow, cytokines and bone remodeling. N Engl J Med 332:305–311, 1995

    Google Scholar 

  15. Manolagas SC: Role of cytokines in bone resorption. Bone 17:63S–67S, 1995

    Google Scholar 

  16. Kusugami K, Fukatsu A, Tanimoto M, Shinoda M, Haruta J-I, Kuroiwa A, et al: Elevation of interleukin-6 in inflammatory bowel disease is macrophage-and epithelial cell-dependent. Dig Dis Sci 40:949–959, 1995

    Google Scholar 

  17. Mahida YR, Kurlak L, Gallagher A, Hawkey CJ: High circulating levels of interleukin 6 in active Crohn' disease, but not ulcerative colitis. Gut 32:1531–1534, 1991

    Google Scholar 

  18. Gross VT, Andus T, Caesar I, Roth M, Schölmerich J: Evidence for continuous stimulation of interleukin-6 production in Crohn' disease. Gastroenterology 102:514–529, 1992

    Google Scholar 

  19. Pollak RD, Karmeli F, Eliakim R, Ackerman Z, Tabb K, Rachmilewitz D: Femoral neck osteopenia in patients with inflammatory bowel disease. Am J Gastroenterol 93:1483–1490, 1998

    Google Scholar 

  20. Fornari MC, Pedreira S, Niveloni S, Gonzalez D, Diez RA, Vazquez H, et al: Pre-and post-treatment serum levels of cytokines IL-1_, IL-6 and IL-1 receptor antagonist in celiac disease. Are they related to the associated osteopenia? Am J Gastroenterol 93:413–418, 1998

    Google Scholar 

  21. De Benedetti F, Massa M, Pignatti P, Albani S, Novick D, Martini A: Serum soluble interleukin 6 (IL-6) receptor and IL-6/soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis. J Clin Invest 93:2114–2119, 1994

    Google Scholar 

  22. Kotake S, Sato K, Kim KJ, Takahashi N, Udagawa N, Nakamura I: Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Min Res 11:88–95, 1996

    Google Scholar 

  23. Pocock NA, Eisman JA, Hopper JC, Yeates MG, Sambrook PN, Eberl S: Genetic determinants of bone mass in adults: A twin study. J Clin Invest 80:706–710, 1987

    Google Scholar 

  24. Krall EA, Dawson-Hughes B: Heritable and life-style determinants of bone mineral density. J Bone Min Res 8:1–9, 1993

    Google Scholar 

  25. Gueguen R, Jouanny P, Guilemin F, Kuntz C, Pourel J, Siest G: Segregation analysis and variance components analysis of bone mineral density in healthy families. J Bone Min Res 12:2017–2022, 1995

    Google Scholar 

  26. Schulte CMS, Dignass AU, Goebell H, Röher H-D, Schulte K-M: Genetic factors determine the extent of bone loss in inflammatory bowel disease. Gastroenterology 119:909–920, 2000

    Google Scholar 

  27. Ray A, Prefontaine KE, Ray P: Down-modulation of interleukin-6 gene expression by 17 beta-estradiol in the absence of high affinity DNA binding by the estrogen receptor. J Biol Chem 269:12940–12946, 1994

    Google Scholar 

  28. Pottratz S, Bellido T, Mocharla H, Crabb D, Manolagas SC: 17β-Estradiol inhibits expression of human interleukin-6 promoter-reporter constructs by a receptor-dependent mechanism. J Clin Invest 93:944–950, 1994

    Google Scholar 

  29. Bellido T, Jilka RL, Boyce BF, Girasole G, Broxmeyer H, Dalrymple SA, et al: Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. J Clin Invest 95:2886–2895, 1995

    Google Scholar 

  30. Poli V, Balena R, Fattori E, Markatos A, Yamamoto M, Tanaka H, et al: Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO J 13:1189–1196, 1994

    Google Scholar 

  31. Jilka RL, Hangoc G, Girasole G, Passeri G, Williams DC, Abrams JS, et al: Increased osteoclast development after estrogen loss: Mediation by interleukin-6. Science 257:88–91, 1992

    Google Scholar 

  32. Hofbauer LC, Lacey DL, Dunstan DL, Spelsberg TC, Riggs BL, Khosla S: Interleukin-1beta and tumor necrosis factoralpha, but not interleukin-6 stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone 25:255–259, 1999

    Google Scholar 

  33. Gratacos J, Collado A, Pons F, Osaba M, Sanmarti R, Roque M, et al: Significant loss of bone mass in patients with early, active ankylosing spondylitis: A follow-up study. Arth Rheum 42:2319–2324, 1999

    Google Scholar 

  34. Hirano T: Interleukin 6 and its receptor: Ten years later. Int Revl Immunol 16:249–284, 1998

    Google Scholar 

  35. van Leeuwen MA, Westra J, Limburg PC, van Riel PL, van Rijswijk MH: Clinical significance of interleukin-6 measurement in early rheumatoid arthritis: Relation with laboratory and clinical variables and radiological progression in a three year prospective study. Ann Rheumatol Dis 54:674–677, 1995

    Google Scholar 

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Schulte, C.M., Goebell, H., Rõher, HD. et al. Genetic Determinants of IL-6 Expression Levels Do Not Influence Bone Loss in Inflammatory Bowel Disease. Dig Dis Sci 46, 2521–2528 (2001). https://doi.org/10.1023/A:1012300609279

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