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Rheumatology International

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01.01.2012 | Original Article

The balance between soluble receptors regulating IL-6 trans-signaling is predictive for the RANKL/osteoprotegerin ratio in postmenopausal women with rheumatoid arthritis

verfasst von: Peter Oelzner, Sybille Franke, Gabriele Lehmann, Thorsten Eidner, Gert Hein, Gunter Wolf

Erschienen in: Rheumatology International | Ausgabe 1/2012

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Abstract

The objective of this study is to investigate the relationship between soluble components of the interleukin 6 (IL-6) system mediating and modifying IL-6 trans-signaling and the RANKL–RANK–osteoprotegerin system in postmenopausal women with rheumatoid arthritis (RA). The following parameters were investigated in 126 postmenopausal women with RA: IL-6, soluble IL-6-receptor (sIL-6R), soluble glycoprotein 130 (sgp130), sRANKL, osteoprotegerin (OPG), osteocalcin, erythrocyte sedimentation rate and C-reactive protein in sera, pyridinolin and desoxypyridinolin crosslinks in the morning urine. Bone mineral density (BMD) was measured by dual X-ray absorptiometry at the lumbar spine (BMD-LS) and at the femoral neck (BMD-FN). Predictors of RANKL/OPG ratio and BMD were evaluated by multiple linear regression analysis. The following determinants of the RANKL/OPG ratio were identified: sIL-6R/sgp130 ratio and daily glucocorticoid (GC) dose as positive determinants in the whole group (R ² = 0.56; P = 0.001), sIL-6R/sgp130 ratio as the exclusive positive determinant in patients with GC therapy (R ² = 0.48; P = 0.001) and sgp130 as negative determinant in patients without GC (R ² = 0.42; P = 0.031). Sgp130 was highly significantly positively correlated with OPG in the whole group (P < 0.001) as well as in patients with (n = 70; P < 0.05) and without GC therapy (n = 56; P < 0.01). sIL-6R was the main negative predictor of BMD-LS (R ² = 0.41; P = 0.019). High sIL-6R/sgp130 ratio and/or low sgp130 are associated with a high sRANKL/OPG ratio in sera of postmenopausal women with RA indicating the critical significance of IL-6 trans-signaling for an increase in the RANKL/OPG ratio and of bone resorption. Inhibition of IL-6 trans-signaling may be an effective bone-protecting principle in postmenopausal women with RA.

Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, Capparelli C, Li J, Elliott R, McCabe S, Wong T, Campagnuolo G, Moran E, Bogoch ER, Van G, Nguyen LT, Ohashi PS, Lacey DL, Fish E, Boyle WJ, Penninger JM (1999) Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402:304–309PubMedCrossRef

Gravallese EM, Manning C, Tsay A, Naito A, Pan C, Amento E, Goldring SR (2000) Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum 43:250–258PubMedCrossRef

Takayanagi H, Iizuka H, Juji T, Nakagawa T, Yamamoto A, Miyazaki T, Koshihara Y, Oda H, Nakamura K, Tanaka S (2000) Involvement of receptor activator of nuclear factor kappaB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum 43:259–269PubMedCrossRef

Schett G, Redlich K, Hayer S, Zwerina J, Bolon B, Dunstan C, Gortz B, Schulz A, Bergmeister H, Kollias G, Steiner G, Smolen JS (2003) Osteoprotegerin protects against generalized bone loss in tumor necrosis factor-transgenic mice. Arthritis Rheum 48:2042–2051PubMedCrossRef

Stolina M, Adamu S, Ominsky M, Dwyer D, Asuncion F, Geng Z, Middleton S, Brown H, Pretorius J, Schett G, Bolon B, Feige U, Zack D, Kostenuik PJ (2005) RANKL is the marker and mediator of local and systemic bone loss in two rat models of inflammatory arthritis. J Bone Miner Res 20:1756–1765PubMedCrossRef

Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, Korb A, Smolen S, Hoffmann M, Scheinecker C, van der Heide D, Landewe R, Lacey D, Richards WG, Schett G (2007) Dickkopf-1 is a master regulator of joint remodeling. Nat Med 13:156–163PubMedCrossRef

Hofbauer LC, Lacey DL, Dunstan CR, Spelsberg TC, Riggs BL, Khosla S (1999) Interleukin-1beta and tumor necrosis factor alpha, but not interleukin-6 stimulate osteoprotegerin ligand gene expression in human osteolastic cells. Bone 25:255–259PubMedCrossRef

Theoleyre S, Wittrant Y, Tat SK, Fortun Y, Redini F, Heymann D (2004) The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev 15:457–475PubMedCrossRef

Kwan Tat S, Padrines M, Theolyre S, Heymann D, Fortun Y (2004) IL-6, RANKL, TNF-alpha/IL-1: interrelation in bone resorption pathophysiology. Cytokine Growth Factor Rev 15:49–60PubMedCrossRef

10.

Hofbauer LC, Gori F, Riggs BL, Lacey DL, Dunstan CR, Spelsberg TC, Khosla S (1999) Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 140:4382–4389PubMedCrossRef

11.

Oelzner P, Müller A, Deschner F, Hüller M, Abendroth K, Hein G, Stein G (1998) Relationship between disease activity and serum levels of vitamin D metabolites and PTH in rheumatoid arthritis. Calcif Tissue Int 62:193–198PubMedCrossRef

12.

Sugiyama T (2001) Involvement of interleukin-6 and prostaglandin E2 in periarticular osteoporosis of postmenopausal women with rheumatoid arthritis. J Bone Miner Res 19:89–96CrossRef

13.

Scheidt-Nave C, Bismar H, Leidig-Bruckner G, Woitge H, Seibel M, Ziegler R, Pfeilschifter J (2001) Serum interleukin 6 is a major predictor of bone loss in women specific to the first decade past menopause. J Endocrinol Metab 86:2032–2042CrossRef

14.

Giuliani N, Sansoni P, Girasole G, Vescovini R, Passeri G, Passeri M, Pedrazzoni M (2001) Serum interleukin-6, soluble interleukin-6 receptor and soluble gp130 exhibit different patterns of age- and menopause-related changes. Exp Gerontol 36:547–557PubMedCrossRef

15.

Rose-John S, Scheller J, Elson G, Jones SA (2006) Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol 80:227–236PubMedCrossRef

16.

Scheller J, Rose-John S (2006) Interleukin-6 and its receptor: from bench to bedside. Med Microbiol Immunol 195:173–183PubMedCrossRef

17.

Richards PJ, Nowell MA, Horiuchi S, McLoughlin RM, Fielding CA, Grau S, Yamamoto N, Ehrmann M, Rose-John S, Williams AS, Jones SA (2006) Functional characterization of a soluble gp130 isofrom and its therapeutic capacity in an experimental model of inflammatory arthritis. Arthritis Rheum 54:1662–1672PubMedCrossRef

18.

Nowell MA, Williams AS, Carty SA, Scheller J, Hayes AJ, Jones GW, Richards PJ, Slinn S, Ernst M, Jenkins BJ, Topley N, Rose-John S, Jones SA (2009) Therapeutic targeting of IL-6 trans-signaling counteracts STAT3 control of experimental inflammatory arthritis. J Immunol 182:613–622PubMed

19.

Arnett FC, Edworthy SM, Bloch DA (1988) The American Rheumatism Association 1987 revised criteria for classification of rheumatoid arthritis. Arthritis Rheum 31:315–324PubMedCrossRef

20.

Lange U, Müller-Ladner U (2007) Glucocorticoid-induced osteoporosis. Z Rheumatol 66:129–136PubMedCrossRef

21.

Müller A, Hein G, Franke S, Herrmann D, Henzgen S, Roth A, Stein G (1996) Quantitative analysis of pyridinium crosslinks of collagen in the synovial fluid of patients with rheumatoid arthritis using high-performance liquid chromatography. Rheumatol Int 16:23–28PubMedCrossRef

22.

Einspruch EL (ed) (2005) An introductory guide to SPSS for windows. Sage, Thousand Oaks, London, New Delhi

23.

Ding C, Parameswaran V, Udayan R, Burgess J, Jones G (2008) Circulating levels of inflammatory markers predict change in bone mineral density and resorption in older adults: a longitudinal study. J Clin Endocrinol Metab 93:1952–1958PubMedCrossRef

24.

Ferrrari SL, Ahn-Luong L, Garnero P, Humphries SE, Greenspan SL (2003) Two promotor polymorphisms regulating interleukin-6 gene expression are associated with circulating levels of c-reactive protein and markers of bone resorption in postmenopausal women. J Endocrinol Metab 88:255–259CrossRef

25.

Tat SK, Pelletier JP, Lajeuinesse D, Fahmi H, Duval N, Martel-Pelletier J (2008) Differential modulation of RANKL isoforms by human osteoarthritic subchondral bone osteoblasts: influence of osteotropic factors. Bone 43:284–291PubMedCrossRef

26.

Nakashima T, Kobayashi Y, Yamasaki S, Kawakami A, Eguchi K, Sasaki H, Sakai H (2000) Protein expression and functional difference of membrane-bound and soluble receptor activator of NFkappaB ligand: modulation of the expression by osteotropic factors and cytokines. Biochem Biophys Res Commun 275:768–775PubMedCrossRef

27.

Palmqvist P, Persson E, Conaway HH, Lerner UH (2002) IL-6, leukaemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF-kappa B ligand, osteoprotegerin, and receptor activator of NF-kappa B in mouse calvariae. J Immunol 169:3353–3362PubMed

28.

Sims NA, Jenkins BJ, Quinn JM, Nakamura A, Glatt M, Gillespie MT, Ernst M, Martin TJ (2004) Glycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways. J Clin Invest 113:379–389PubMed

29.

Sims NA (2009) Gp130 signaling in bone cell biology: multiple roles revealed by analysis of genetically altered mice. Mol Cell Endocrinol 310:30–39PubMedCrossRef

30.

Poli V, Balena R, Fattori E, Markatos A, Yamamoto M, Tanaka H, Ciliberto G, Roadan GA, Costantini F (1994) Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO J 13:1189–1196PubMed

31.

Hayashi M, Rho MC, Enomoto A, Fukami A, Kim YP, Kikuchi Y, Sunazaka T, Hirose T, Komiyama K, Omura S (2002) Suppression of bone resorption by madindoline A, a novel nonpeptide antagonist to gp130. Proc Natl Acad Sci USA 99:14728–14733PubMedCrossRef

32.

Shin HI, Divieti P, Sims NA, Kobayashi T, Miao D, Karapalis A, Baron R, Bringhurst R, Kronenberg HM (2004) Gp130-mediated signalling is necessary for normal osteoblastic function in vivo and in vitro. Endocrinology 145:1376–1385PubMedCrossRef

33.

Grey A, Mitnick MA, Masiukiewicz U, Sun BH, Rudikoff S, Jilka RL, Manolagas SC, Insogna K (1999) A role of interleukin-6 in parathyroid hormone-induced bone resorption in vivo. Endocrinology 140:4683–4690PubMedCrossRef

34.

Wong PK, Quinn JM, Sims NA, van Nieuwenhuijze A, Campbell IK, Wicks IP (2006) Interleukin-6 modulates production of T-lymphocyte-derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis. Arthritis Rheum 54:158–168PubMedCrossRef

35.

Vermes C, Jacobs JJ, Zhang J, Firneisz G, Roebuck KA, Glant TT (2002) Shedding of the interleukin-6 (IL-6) receptor (gp80) determines the ability of IL-6 to induce gp130 phosphorylation in human osteoblasts. J Biol Chem 277:16879–16887PubMedCrossRef

36.

Tamura T, Udagawa N, Takahashi N, Miyaura C, Tanaka S, Yamada Y, Koishihara Y, Ohsugi Y, Kumaki K, Taga T et al (1993) Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci USA 90:11924–11928PubMedCrossRef

37.

Kotake S, Sato K, Kim KJ, Takahashi N, Udagawa N, Nakamura I, Yamaguchi A, Kishimoto T, Suda T, Kashiwazaki S (1996) Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res 11:88–95PubMedCrossRef

38.

Liu XH, Kirschenbaum SA, Yao S, Levine AC (2005) Crosstalk between the interleukin-6 and prostaglandin E(2) signaling systems results in enhancement of osteoclastogenesis through effects on the osteoprotegerin/receptor activator of nuclear factor-(kappa)B (RANK) ligand/RANK system. Endocrinology 146:1991–1998PubMedCrossRef

39.

Liu XH, Kirschenbaum A, Yao S, Levine AC (2006) Interactive effect of interleukin-6 and prostaglandin E2 on osteoclastogenesis via the OPG/RANKL/RANK system. Ann Acad Sci 1068:225–233CrossRef

40.

Sanchez C, Gabay O, Salvat C, Henrotin YE, Berenbaum F (2009) Mechanical loading highly increases IL-6 production and decreases OPG expression by osteoblasts. Osteoarthr Cartil 17:473–481PubMedCrossRef

41.

Mossetti G, Rendina D, De Filippo G, Viceconti R, Di Domenico G, Cioffi M, Postiglione L, Nunziata V (2005) Interleukin-6 and osteoprotegerin systems in Paget’s disease of bone: relationship to risedronate treatment. Bone 36:540–554CrossRef

42.

Tsangari H, Findlay DM, Kuliwaba JS, Atkins GJ, Fazzalari NL (2004) Increased expression of IL-6 and RANK mRNA in human trabecular bone from fragility fracture of the femoral neck. Bone 35:334–342PubMedCrossRef

43.

Nakchbandi IA, Lang R, Kinder B, Insogna KL (2008) The role of the receptor activator of nuclear factor-kappaB ligand/osteoprotegerin cytokine system in primary hyperparathyroidism. J Clin Endocrinol Metab 93:967–973PubMedCrossRef

44.

Insogna K, Mitnick M, Pascarella J, Nakchbandi I, Grey A, Masiukiewicz U (2002) Role of the interleukin-6/interleukin-6 soluble receptor cytokine system in mediating increased skeletal sensitivity to parathyroid hormone in perimenopausal women. J Bone Miner Res 17(Suppl 2):N108–N116PubMed

45.

Angeli A, Dovio A, Sartori ML, Masera RG, Ceoloni B, Prolo P, Racca S, Chiappelli F (2002) Interactions between glucocorticoids and cytokines in the bone microenvironment. Ann NY Acad Sci 966:97–107PubMedCrossRef

46.

Polgar A, Brozik M, Toth S, Holub M, Falus A (2002) A synthetic corticosteroid, dexamethasone regulates generation of soluble form of interleukin-6 receptor of human lymphocytes, in vitro. Acta Biol Hung 53:307–315PubMedCrossRef

47.

Murakami-Mori K, Mori S, Taga T, Kishimoto T, Nakamura S (1997) Enhancement of gp130-mediated tyrosine phosphorylation of STAT3 and its DNA-binding activity in dexamethasone-treated AIDS-associated Kaposi`s sarcoma cells: selective synergy between dexamethasone and gp130-related growth factors in Kaposi`s sarcoma cell proliferation. J Immunol 158:5518–5526PubMed

48.

Takeda T, Kurachi H, Yamamoto T, Nishio Y, Nakatsuji Y, Morishige K-i, Miyake A, Murata Y (1998) Crosstalk between the interleukin-(IL-6)-JAK-STAT and the glucocorticoid-nuclear receptor pathway: synergistic activation of IL-6 response element by IL-6 and glucocorticoid. J Endocrinol 159:323–330PubMedCrossRef

49.

Dovio A, Perazzolo L, Saba L, Termine A, Capobianco M, Bertolotto A, Angeli A (2006) High dose glucocorticoids increase serum levels of soluble IL-6 receptor alpha and its ratio to soluble gp130: an additional mechanism for early increased bone resorption. Eur J Endocrinol 154:745–751PubMedCrossRef

Titel: The balance between soluble receptors regulating IL-6 trans-signaling is predictive for the RANKL/osteoprotegerin ratio in postmenopausal women with rheumatoid arthritis
verfasst von: Peter Oelzner
Sybille Franke
Gabriele Lehmann
Thorsten Eidner
Gert Hein
Gunter Wolf
Publikationsdatum: 01.01.2012
Verlag: Springer-Verlag
Erschienen in: Rheumatology International / Ausgabe 1/2012
Print ISSN: 0172-8172
Elektronische ISSN: 1437-160X
DOI: https://doi.org/10.1007/s00296-010-1606-z

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The balance between soluble receptors regulating IL-6 trans-signaling is predictive for the RANKL/osteoprotegerin ratio in postmenopausal women with rheumatoid arthritis

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