Increased expression of receptor activator of NF-kappa B ligand (RANKL), its receptor RANK and its decoy receptor osteoprotegerin in the colon of Crohn's disease patients
[en] Crohn's disease (CD) is associated with low bone mass due to chronic inflammation and other factors. Receptor activator of NF-kappaB ligand (RANKL), its receptor RANK and its decoy receptor osteoprotegerin (OPG) are potentially involved in this process as they regulate osteoclastogenesis and are influenced by pro-inflammatory cytokines. The aim of this study was to determine the levels of soluble RANKL (sRANKL), RANK and OPG expression both in the serum and in the colon of CD patients. Levels of sRANKL and OPG were assessed in the serum and the supernatants of cultured colonic biopsies in patients with CD and controls by ELISA. RANK expression was explored by immunostaining and immunofluorescence of fixed colonic samples. OPG and sRANKL levels were higher in the serum of CD patients as compared to age- and sex-matched controls. Levels of sRANKL and OPG were significantly enhanced in cultured colonic biopsies from CD, and OPG levels correlated with histological inflammation, and pro- and anti-inflammatory cytokine levels. No significant correlation was found for sRANKL. RANK(+) cells were increased in the colon of CD, particularly in inflamed areas. These cells were positive for CD68 or S100 protein. We conclude that serum and local levels of sRANKL and OPG are increased in CD. Moreover, RANK is expressed in the colonic mucosa by subpopulations of activated macrophages or dendritic cells at higher levels in CD compared to normal colon.
Disciplines :
Immunology & infectious disease
Author, co-author :
Franchimont, N.
Reenaers, Catherine ; Université de Liège - ULiège > Département des sciences cliniques > Rhumatologie
Lambert, Chantal ; Centre Hospitalier Universitaire de Liège - CHU > Anatomie pathologique
Belaiche, Jacques ; Université de Liège - ULiège > Département des sciences cliniques > Hépato-gastroentérologie
Bours, Vincent ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Génétique générale et humaine
Malaise, Michel ; Université de Liège - ULiège > Département des sciences cliniques > Rhumatologie
Delvenne, Philippe ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Louis, Edouard ; Université de Liège - ULiège > Département des sciences cliniques > Hépato-gastroentérologie
Language :
English
Title :
Increased expression of receptor activator of NF-kappa B ligand (RANKL), its receptor RANK and its decoy receptor osteoprotegerin in the colon of Crohn's disease patients
Fiocchi C. Inflammatory Bowel Disease: Etiology and pathogenesis. Gastroenterology 1998; 115:182-205.
Schreiber S, Nikolaus S, Hampe J. Activation of nuclear factor kappa B in inflammatory bowel disease. Gut 1998; 42:477-84.
Romagnani P, Annunziato F, Baccari MC, Paronchi P. T Cells and cytokines in Crohn's disease. Current Opin Immunol 1997; 9:793-9.
Jahnsen J, Falch J, Aadland E, Mowinckel P. Bone mineral density is reduced in patients with Crohn's disease but not in patients with ulcerative colitis: a population based study. Gut 1997; 40:313-9.
Ghosh S, Cowen S, Hannan W, Ferguson A. Low bone mineral density in Crohn's disease, but not in ulcerative colitis at diagnosis. Gastroenterology 1994; 107:1031-9.
Vestergaard P, Krogh K, Rejnmark L, Laurberg S, Mosekilde L. Fracture risk is increased in Crohn's disease but not in ulcerative colitis. Gut 2000; 46:176-81.
Bernstein CN, Blanchard JF, Leslie W, Wajda A, Yu BN. The incidence of fracture among patients with inflammatory bowel disease. A population-based cohort study. Ann Intern Med 2000; 133:795-9.
Klaus J, Armbrecht G, Steinkamp M et al. High prevalence of vertebral fracture in patients with Crohn's disease. Gut 2002; 51:654-8.
Van Staa TP, Cooper C, Brusse LS, Leufkens H, Javaid MK, Arden NK. Inflammatory bowel disease and the risk of fracture. Gastroenterology 2003; 125:1591-7.
Bernstein CN, Leslie WD. The pathophysiology of bone disease in gastrointestinal disease. Eur J Gastroenterol Hepatol 2003; 15:857-64.
Kong YY, Feige U, Sarosi I et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999; 402:304-9.
Walsh MC, Choi X. Biology of the TRANCE axis. Cytokine Growth Factor Rev 2003; 14:251-63.
Anderson DM, Maraskovsky E, Billingsley WL et al. A homologue of TNF receptor and its ligand enhance T-cell growth an dendritic-cell function. Nature 1997; 390:175-9.
Theill LE, Boyle WJ, Penninger JM. RANKL and RANK: T Cells bone loss and mammalian evolution. Annu Rev Immunol 2002; 20:795-823.
Simonet WS, Lacey DL, Dunstan CR et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89:309-19.
Yun TJ, Chaudhary PM, Shu GL et al. OPG/FDCR-1, a TNF receptor family member, is expressed in lymphoid cells and is up-regulted by ligating CD40. J Immunol 1998; 161:6113-21.
Green EA, Flavell RA. TRANCE-RANK, a new signal pathway involved in lymphocyte development and T Cell activation. J Exp Med 1999; 189:1017-20.
Cremer I, Dieu-Nosjean MC, Maréchal S et al. Long-lived immature dendritic cells mediated by TRANCE-RANK interaction. Blood 2002; 100:3646-55.
Josien R, Wong BR, Li HL, Steinman RF, Choi Y. TRANCE, a TNF family member, is differentially expressed on T Cell subsets and induces cytokine production in dendritic cells. J Immunol 1999; 162:2562-8.
Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study. Gastroenterol 1976; 70:439-44.
Reimund JM, Wittersheim C, Dumont S, Muller CD, Kennet JS, Baumann R, Poindron P, Duclos B. Increased production of tumor necrosis factor-α, interleukin-1β, and interleukin-6 by morphologically normal intestinal biopsies from patients with Crohn's disease. Gut 1996; 39:684-9.
Wardle TD, Hall L, Turnberg LA. Use of coculture of colonic biopsies to investigate the release of eicosanoids by inflamed and uninflamed mucosa from patients with inflammatory bowel disease. Gut 1992; 33:1644-51.
Bosari S, Lee AK, DeLellis RA, Wiley BD, Heatley GJ, Silverman ML. Microvessel quantitation and prognosis in invasive breast carcinoma. Hum Pathol 1992; 23:755-61.
Pender SLF, Tickle SP, Docherty AJP, Howie D, Wathen NC, McDonald TT. A major role for matrix metalloproteinases in T cell injury in the gut. J Immunol 1997; 158:1582-90.
von Tripitz C, Epp S, Klaus J et al. Effect of systemic glucocorticoid therapy on bone metabolism and the osteoprotegerin system in patients with active Crohn's disease. Eur J Gastroenterol Hepatol 2003; 15:1165-70.
Hofbauer LC, Schoppet M. Serum measurement of osteoprotegerin-clinical relevance and potential application. Eur J Endocrinol 2001; 145:681-3.
Saidenberg Kermanac'h N, Bessis N, Cohen-Sola IM, De Vernejoul MC, Boissier MC. Osteoprotegerin and inflammation. Eur Cytokines Netw 2002; 13:144-53.
Liu Z, Colpaert S, D'Haens G, Kasran A, de Boer M, Rutgeerts P, Geboes K, Ceuppens JL. Hyperexpression of CD40 ligand (CD154) in inflammatory bowel disease and its contribution to pathogenic cytokine production. J Immunol 1999; 163:4049-57.
Wong BR, Rho J, Arron J et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminale kinase in T cells. J Biol Chem 1997; 272:25190-4.
Josien BR, Li HL, Ingulli E, Sarma S, Wong BR, Vologodskaia M, Steinman RM, Choi Y. TRANCE, a tumor necrosis factor family member, enhances the longevity and adjuvant properties of dendritic cells In vivo. J Exp Med 2000; 191:495-502.
Boirivant M, Marini M, Di Felice G, Pronio AM, Montesani C, Tersigni R, Strober W. Lamina propria T cells in Crohn's disease and other gastrointestinal inflammation show defective CD2 pathway-induced apoptosis. Gastroenterology 1999; 116:557-65.
Ina K, Itoh J, Fukushima K et al. Resistance of Crohn's disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance. J Immunol 1999; 163:1081-90.
te Velde AA, van Kooyk Y, Braat H, Hommes DW, Dellemijn TA, Slors JF, van Deventer SJ, Vyth-Dreese FA. Increased expression of DC-SIGN+IL-12+IL-18+ and CD83+IL-12-IL-18- dendritic cell populations in the colonic mucosa of patients with Crohn's disease. Eur J Immunol 2003; 33:143-51.
Sarsfield P, Jones DB, Wright DH. Accessory cells in Crohn's disease of the terminal ileum. Histopathology 1996; 28:213-9.
Ashcroft AJ, Cruickshank SM, Croucher PI et al. Colonic dendritic cells, intestinal inflammation, and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin. Immunity 2003; 19:849-61.
Emery JG, McDonnell P, Brigham Burke M et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998; 273:14363-7.
MacFarlane M. TRAIL-induced signalling and apoptosis. Toxicol Lett 2003; 139:89-97.
