title: The balance between soluble receptors regulating IL-6 trans-signaling is predictive for the RANKL/osteoprotegerin ratio in postmenopausal women with rheumatoid arthritis.
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.
authors.affiliation: Division of Rheumatology/Osteology, Department of Internal Medicine III, Friedrich-Schiller-University of Jena, Erlanger Allee 101, 07740 Jena, Germany. peter.oelzner@med.uni-jena.de
authors.forename: Peter
authors.initials: P
authors.lastname: Oelzner
authors.forename: Sybille
authors.initials: S
authors.lastname: Franke
authors.forename: Gabriele
authors.initials: G
authors.lastname: Lehmann
authors.forename: Thorsten
authors.initials: T
authors.lastname: Eidner
authors.forename: Gert
authors.initials: G
authors.lastname: Hein
authors.forename: Gunter
authors.initials: G
authors.lastname: Wolf
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000502:physiology; D050822:Cytokine Receptor gp130 / Q000097:blood; D005260:Female; D005938:Glucocorticoids / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D016014:Linear Models; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000097:blood / Q000139:chemically induced / Q000453:epidemiology; D053244:Osteoprotegerin / Q000097:blood*; D017698:Postmenopause / Q000097:blood*; D011237:Predictive Value of Tests; D053245:RANK Ligand / Q000097:blood*; D019947:Receptors, Interleukin-6 / Q000097:blood*; D012307:Risk Factors; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D015415:Biomarkers; D005938:Glucocorticoids; D015850:Interleukin-6; D053244:Osteoprotegerin; D053245:RANK Ligand; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130
references.citation: Rheumatol Int. 1996;16(1):23-8
references.pmid: 8783419
references.citation: Ann N Y Acad Sci. 2002 Jun;966:97-107
references.pmid: 12114264
references.citation: Endocrinology. 1999 Oct;140(10):4382-9
references.pmid: 10499489
references.citation: J Immunol. 2002 Sep 15;169(6):3353-62
references.pmid: 12218157
references.citation: Calcif Tissue Int. 1998 Mar;62(3):193-8
references.pmid: 9501950
references.citation: Nature. 1999 Nov 18;402(6759):304-9
references.pmid: 10580503
references.citation: Arthritis Rheum. 1988 Mar;31(3):315-24
references.pmid: 3358796
references.citation: J Immunol. 1997 Jun 1;158(11):5518-26
references.pmid: 9164976
references.citation: Osteoarthritis Cartilage. 2009 Apr;17(4):473-81
references.pmid: 18974013
references.citation: J Clin Endocrinol Metab. 2008 Mar;93(3):967-73
references.pmid: 18073309
references.citation: Ann N Y Acad Sci. 2006 Apr;1068:225-33
references.pmid: 16831922
references.citation: Endocrinology. 2004 Mar;145(3):1376-85
references.pmid: 14617570
references.citation: J Immunol. 2009 Jan 1;182(1):613-22
references.pmid: 19109195
references.citation: Acta Biol Hung. 2002;53(3):307-15
references.pmid: 12371610
references.citation: Cytokine Growth Factor Rev. 2004 Feb;15(1):49-60
references.pmid: 14746813
references.citation: Med Microbiol Immunol. 2006 Dec;195(4):173-83
references.pmid: 16741736
references.citation: J Leukoc Biol. 2006 Aug;80(2):227-36
references.pmid: 16707558
references.citation: EMBO J. 1994 Mar 1;13(5):1189-96
references.pmid: 8131749
references.citation: Bone. 1999 Sep;25(3):255-9
references.pmid: 10495128
references.citation: Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11924-8
references.pmid: 8265649
references.citation: J Clin Endocrinol Metab. 2008 May;93(5):1952-8
references.pmid: 18285417
references.citation: Arthritis Rheum. 2006 Jan;54(1):158-68
references.pmid: 16385511
references.citation: Cytokine Growth Factor Rev. 2004 Dec;15(6):457-75
references.pmid: 15561602
references.citation: Mol Cell Endocrinol. 2009 Oct 30;310(1-2):30-9
references.pmid: 18805458
references.citation: Endocrinology. 1999 Oct;140(10):4683-90
references.pmid: 10499526
references.citation: Bone. 2004 Jul;35(1):334-42
references.pmid: 15207775
references.citation: Exp Gerontol. 2001 Mar;36(3):547-57
references.pmid: 11250125
references.citation: Biochem Biophys Res Commun. 2000 Sep 7;275(3):768-75
references.pmid: 10973797
references.citation: Eur J Endocrinol. 2006 May;154(5):745-51
references.pmid: 16645023
references.citation: J Clin Invest. 2004 Feb;113(3):379-89
references.pmid: 14755335
references.citation: J Bone Miner Res. 2002 Nov;17 Suppl 2:N108-16
references.pmid: 12412787
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14728-33
references.pmid: 12417753
references.citation: J Bone Miner Res. 2005 Oct;20(10):1756-65
references.pmid: 16160733
references.citation: Bone. 2008 Aug;43(2):284-91
references.pmid: 18539107
references.citation: Bone. 2005 Mar;36(3):549-54
references.pmid: 15777635
references.citation: J Bone Miner Res. 1996 Jan;11(1):88-95
references.pmid: 8770701
references.citation: J Clin Endocrinol Metab. 2001 May;86(5):2032-42
references.pmid: 11344203
references.citation: Arthritis Rheum. 2003 Jul;48(7):2042-51
references.pmid: 12847699
references.citation: Arthritis Rheum. 2000 Feb;43(2):250-8
references.pmid: 10693863
references.citation: J Biol Chem. 2002 May 10;277(19):16879-87
references.pmid: 11884403
references.citation: J Bone Miner Metab. 2001;19(2):89-96
references.pmid: 11281165
references.citation: Z Rheumatol. 2007 Mar;66(2):129-36; quiz 137-8
references.pmid: 17334736
references.citation: Endocrinology. 2005 Apr;146(4):1991-8
references.pmid: 15618359
references.citation: Nat Med. 2007 Feb;13(2):156-63
references.pmid: 17237793
references.citation: J Endocrinol. 1998 Nov;159(2):323-30
references.pmid: 9795374
references.citation: Arthritis Rheum. 2006 May;54(5):1662-72
references.pmid: 16646038
references.citation: Arthritis Rheum. 2000 Feb;43(2):259-69
references.pmid: 10693864
references.citation: J Clin Endocrinol Metab. 2003 Jan;88(1):255-9
references.pmid: 12519862