The balance between soluble receptors regulating IL-6 trans-signaling is predictive for the RANKL/osteoprotegerin ratio in postmenopausal women with rheumatoid arthritis.
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.
Oelzner
Peter
P
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
Franke
Sybille
S
Lehmann
Gabriele
G
Eidner
Thorsten
T
Hein
Gert
G
Wolf
Gunter
G
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*
D015415:Biomarkers; D005938:Glucocorticoids; D015850:Interleukin-6; D053244:Osteoprotegerin; D053245:RANK Ligand; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130
Rheumatol Int. 1996;16(1):23-8
8783419
Ann N Y Acad Sci. 2002 Jun;966:97-107
12114264
Endocrinology. 1999 Oct;140(10):4382-9
10499489
J Immunol. 2002 Sep 15;169(6):3353-62
12218157
Calcif Tissue Int. 1998 Mar;62(3):193-8
9501950
Nature. 1999 Nov 18;402(6759):304-9
10580503
Arthritis Rheum. 1988 Mar;31(3):315-24
3358796
J Immunol. 1997 Jun 1;158(11):5518-26
9164976
Osteoarthritis Cartilage. 2009 Apr;17(4):473-81
18974013
J Clin Endocrinol Metab. 2008 Mar;93(3):967-73
18073309
Ann N Y Acad Sci. 2006 Apr;1068:225-33
16831922
Endocrinology. 2004 Mar;145(3):1376-85
14617570
J Immunol. 2009 Jan 1;182(1):613-22
19109195
Acta Biol Hung. 2002;53(3):307-15
12371610
Cytokine Growth Factor Rev. 2004 Feb;15(1):49-60
14746813
Med Microbiol Immunol. 2006 Dec;195(4):173-83
16741736
J Leukoc Biol. 2006 Aug;80(2):227-36
16707558
EMBO J. 1994 Mar 1;13(5):1189-96
8131749
Bone. 1999 Sep;25(3):255-9
10495128
Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11924-8
8265649
J Clin Endocrinol Metab. 2008 May;93(5):1952-8
18285417
Arthritis Rheum. 2006 Jan;54(1):158-68
16385511
Cytokine Growth Factor Rev. 2004 Dec;15(6):457-75
15561602
Mol Cell Endocrinol. 2009 Oct 30;310(1-2):30-9
18805458
Endocrinology. 1999 Oct;140(10):4683-90
10499526
Bone. 2004 Jul;35(1):334-42
15207775
Exp Gerontol. 2001 Mar;36(3):547-57
11250125
Biochem Biophys Res Commun. 2000 Sep 7;275(3):768-75
10973797
Eur J Endocrinol. 2006 May;154(5):745-51
16645023
J Clin Invest. 2004 Feb;113(3):379-89
14755335
J Bone Miner Res. 2002 Nov;17 Suppl 2:N108-16
12412787
Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14728-33
12417753
J Bone Miner Res. 2005 Oct;20(10):1756-65
16160733
Bone. 2008 Aug;43(2):284-91
18539107
Bone. 2005 Mar;36(3):549-54
15777635
J Bone Miner Res. 1996 Jan;11(1):88-95
8770701
J Clin Endocrinol Metab. 2001 May;86(5):2032-42
11344203
Arthritis Rheum. 2003 Jul;48(7):2042-51
12847699
Arthritis Rheum. 2000 Feb;43(2):250-8
10693863
J Biol Chem. 2002 May 10;277(19):16879-87
11884403
J Bone Miner Metab. 2001;19(2):89-96
11281165
Z Rheumatol. 2007 Mar;66(2):129-36; quiz 137-8
17334736
Endocrinology. 2005 Apr;146(4):1991-8
15618359
Nat Med. 2007 Feb;13(2):156-63
17237793
J Endocrinol. 1998 Nov;159(2):323-30
9795374
Arthritis Rheum. 2006 May;54(5):1662-72
16646038
Arthritis Rheum. 2000 Feb;43(2):259-69
10693864
J Clin Endocrinol Metab. 2003 Jan;88(1):255-9
12519862