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Soluble receptor activator of NFkappa B-ligand and osteoprotegerin in rheumatoid arthritis - relationship with bone mineral density, disease activity and bone turnover

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Abstract

The aim of our study was to investigate determinants of bone mineral density (BMD) measured by dual X-ray absorptiometry at the lumbar spine (BMD-LS) and at the femoral neck (BMD-FN) in patients with rheumatoid arthritis (RA) with special respect to bone resorbing proinflammatory cytokines and their physiological antagonists. In 142 RA patients the following parameters were measured in parallel with BMD: serum levels of soluble receptor activator of nuclear factor kappa-B-ligand (sRANKL), osteoprotegerin (OPG), interleukin (IL)-6, soluble glycoprotein 130 (sgp130), 25-hydroxyvitamin D3 (25OHD3), 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), intact parathyroid hormone, osteocalcin, ionized calcium, renal excretion of pyridinolin and deoxypyridinolin, C-reactive protein, and erythrocyte sedimentation rate (ESR). No significant differences of sRANKL, OPG, IL-6, and spg130 were found between patients with osteoporosis (47.9% of patients), osteopenia (36.6%), and normal BMD (15.5%). However, total sRANKL was significantly higher in postmenopausal women with osteoporosis at FN than in those without (p < 0.05) and showed a negative correlation with BMD-LS in patients older than 60 years (p = 0.01). BMD-LS and BMD-FN (p < 0.001) and total sRANKL (p < 0.01) were negatively related with the age of the patients. Only IL-6 (positive correlation, p < 0.001) and 1,25(OH)2D3 (negative correlation, p < 0.001) but not sRANKL, OPG, and sgp130 were related to disease activity. Using multiple linear regression analysis, menopause was identified as the crucial negative determinant of BMD-LS (R 2 = 0.94, p = 0.001), whereas cumulative glucocorticoid dose (β = −0.80, p = 0.001) and ESR (β = −0.44, p = 0.016) were the negative determinants of BMD-FN (R 2 = 0.86, p = 0.001). The results indicate that influences of age and gender must be considered in investigations on the relationship between BMD and sRANKL in RA and that high serum levels of sRANKL seems to be associated with osteoporosis only in subgroups of RA patients.

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References

  1. Gough A, Sambrook P, Devlin J, Huisson A, Njeh C, Robbins S, Nguyen T, Emery P (1998) Osteoclastic activation is the principal mechanism leading to secondary osteoporosis in rheumatoid arthritis. J Rheumatol 25:1282–1289

    CAS  PubMed  Google Scholar 

  2. Romas E, Gillespie MT, Martin TJ (2002) Involvement of receptor activator of NfkappaB ligand and tumor necrosis factor-alpha in bone destruction in rheumatoid arthritis. Bone 30:340–346

    Article  CAS  PubMed  Google Scholar 

  3. Gough AK, Lilley J, Eyre S, Holder RL, Emery P (1994) Generalised bone loss in patients with early rheumatoid arthritis. Lancet 344:23–27

    Article  CAS  PubMed  Google Scholar 

  4. Henderson NK, Sambrook PN (1996) Relationship between osteoporosis and arthritis and effect of corticosteroids and other drugs on bone. Curr Opin Rheumatol 8:365–369

    Article  CAS  PubMed  Google Scholar 

  5. Henderson CJ, Cawkwell GD, Specker BL, Sierra RI, Wilmott RW, Campaigne BN, Lovell DJ (1997) Predictors of total body bone mineral density in non-corticosteroid-treated prepubertal children with juvenile rheumatoid arthritis. Arthritis Rheum 40:1967–1975

    Article  CAS  PubMed  Google Scholar 

  6. Pepmueller PH, Cassidy JT, Allen SH, Hillman LS (1996) Bone mineralization and bone mineral metabolism in children with juvenile rheumatoid arthritis. Arthritis Rheum 39:746–757

    Article  CAS  PubMed  Google Scholar 

  7. Laan RF, van Reil PL, van Earning LJ, Lemmens AM, Ruijs SH, van de Putte LB (1992) Vertebral osteoporosis in rheumatoid arthritis patients: effect of low dose prednisolone therapy. Br J Rheumatol 31:91–96

    Article  CAS  PubMed  Google Scholar 

  8. Laan RF, van de Putte LB, van Reil PL, van Earning LJ, van’t Hof MA, Lemmens AM (1993) Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid arthritis. Ann Intern Med 119:963–968

    Article  CAS  PubMed  Google Scholar 

  9. Hall GM, Spector TD, Griffin AJ, Jawad AS, Hall ML, Doyle DV (1993) The effect of rheumatoid arthritis and steroid therapy on bone density in postmenopausal women. Arthritis Rheum 36:1510–1516

    Article  CAS  PubMed  Google Scholar 

  10. Kröger H, Honkanen R, Saarikoski S, Alhava E (1994) Decreased axial bone mineral density in perimenopausal women with rheumatoid arthritis—a population based study. Ann Rheum Dis 53:18–23

    Article  PubMed  PubMed Central  Google Scholar 

  11. Michel BA, Bloch DA, Fries JF (1991) Predictors of fractures in early rheumatoid arthritis. J Rheumatol 18:804–808

    CAS  PubMed  Google Scholar 

  12. Sambrook PN, Eisman JA, Champion JD, Yeates MD, Pocock NA, Ebrl S (1987) Determinants of axial bone loss in rheumatoid arthritis. Arthritis Rheum 30:721–728

    Article  CAS  PubMed  Google Scholar 

  13. Michel BA, Bloch DA, Wolfe F, Fries JF (1993) Fractures in rheumatoid arthritis: an evaluation of associated risk factors. J Rheumatol 20:1666–1669

    CAS  PubMed  Google Scholar 

  14. Sambrook PN, Eisman JA, Champion JD, Pocock NA, Yeates MD, Ebrl S (1986) Osteoporosis in rheumatoid arthritis: safety of low dose corticosteroids. Ann Rheum Dis 45:950–953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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 62:193–198

    Article  CAS  PubMed  Google Scholar 

  16. 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 140:4382–4389

    Article  CAS  PubMed  Google Scholar 

  17. 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 36:547–557

    Article  CAS  PubMed  Google Scholar 

  18. Shimizu S, Shiozawa S, Shiozawa K, Imura S, Fujita T (1985) Quantitative histologic studies on the pathogenesis of periarticular osteoporosis in rheumatoid arthritis. Arthritis Rheum 28:25–31

    Article  CAS  PubMed  Google Scholar 

  19. Kroger H, Arnala I, Rehnberg V, Hamalainen M, Alhava E (1994) Histomorphometry of periarticular bone in rheumatoid arthritis. Ann Chir Gynaecol 83:56–62

    CAS  PubMed  Google Scholar 

  20. Tanabe M, Ochi T, Tomita T, Suzuki R, Sakata T, Shimaoka Y, Nakagawa S, Ono K (1994) Remarkable elevation of interleukin 6 and interleukin 8 levels in the bone marrow serum of patients with rheumatoid arthritis. J Rheumatol 21:830–835

    CAS  PubMed  Google Scholar 

  21. Toritsuka Y, Nakamura N, Lee SB, Hashimoto J, Yasui N, Shino K, Ochi T (1997) Osteoclastogenesis in iliac bone marrow of patients with rheumatoid arthritis. J Rheumatol 24:1690–1696

    CAS  PubMed  Google Scholar 

  22. Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Boyle WJ, Riggs BL (2000) The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 15:2–12

    Article  CAS  PubMed  Google Scholar 

  23. Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Goto M, Mochizuki SI, Tsuda E, Morinaga T, Udagawa N, Takahashi N, Suda T, Higashio K (1999) A novel molecular mechanism modulating osteoclast differentiation and function. Bone 25:109–113

    Article  CAS  PubMed  Google Scholar 

  24. 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 43:250–258

    Article  CAS  PubMed  Google Scholar 

  25. 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 43:259–269

    Article  CAS  PubMed  Google Scholar 

  26. 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 402:304–309

    Article  CAS  PubMed  Google Scholar 

  27. 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 48:2042–2051

    Article  CAS  PubMed  Google Scholar 

  28. Saidenberg-Kermanach N, Corrado A, Lemeiter D, de Vernejoul MC, Boissier MC, Cohen-Solal ME (2004) TNF-alpha antibodies and osteoprotegerin decrease systemic bone loss associated with inflammation through distinct mechanisms in collagen-induced arthritis. Bone 35:1200–1207

    Article  CAS  Google Scholar 

  29. Vidal NO, Brandstrom H, Jonsson KB, Ohlsson C (1998) Osteoprotegerin mRNA is expressed in primary human osteoblast-like cells: down-regulation by glucocorticoids. J Endocrinol 159:191–195

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. 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 16:23–28

    Article  PubMed  Google Scholar 

  32. Einspruch EL (ed) (2005) An introductory guide to SPSS for windows. Sage Publications, Thousand Oaks, CA, USA

  33. Furumitsu Y, Inaba M, Yukioka K, Yukioka M, Kumeda Y, Azuma Y, Ohta T, Ochi T, Nishizawa Y, Morii H (2000) Levels of serum and synovial fluid pyridinium crosslinks in patients with rheumatoid arthritis. J Rheumatol 27:64–70

    CAS  PubMed  Google Scholar 

  34. Kaufmann J, Mueller A, Voigt A, Carl HD, Gursche A, Zacher J, Stein G, Hein G (2003) Hydroxypyridinium collagen crosslinks in serum, urine, synovial fluid and synovial tissue in patients with rheumatoid arthritis compared with osteoarthritis. Rheumatology 42:314–320

    Article  CAS  PubMed  Google Scholar 

  35. Masi L, Simonini G, Piscitelli E, Del Monte F, Giani T, Cimaz R, Vierucci S, Brandi ML, Falcini F (2004) Osteoprotegerin (OPG)/RANK-L system in juvenile idiopathic arthritis: is there a potential modulating role for OPG/RANK-L in bone injury? J Rheumatol 31:986–991

    CAS  PubMed  Google Scholar 

  36. Feuerherm AJ, Borset M, Seidel C, Sundan A, Leistad L, Ostensen M, Faxvaag A (2001) Elevated levels of osteoprotegerin (OPG) and hepatocyte growth factor (HGF) in rheumatoid arthritis. Scand J Rheumatol 30:229–234

    Article  CAS  PubMed  Google Scholar 

  37. Ziolkowska M, Kurowska M, Radzikowska A, Luszczykiewicz G, Wiland P, Dziewczopolski W, Filipowicz-Sosnowska A, Pazdur J, Szechinki J, Kowalczewski J, Rell-Bakalarska M, Maslinski W (2002) High levels of osteoprotegerin and soluble receptor activator of nuclear factor kappa B ligand in serum of rheumatoid arthritis patients and their normalization after anti-tumor necrosis factor alpha treatment. Arthritis Rheum 46:1744–1753

    Article  CAS  PubMed  Google Scholar 

  38. Lange U, Teichmann J, Muller-Ladner U, Strunk J (2005) Increase in bone mineral density of patients with rheumatoid arthritis treated with anti-TNF-{alpha} antibody: a prospective open-label pilot study. Rheumatology 44:1546–1548

    Article  CAS  PubMed  Google Scholar 

  39. Landewe RBM, Geusens P, Boers M, Garnero P, van der Heijde D, van der Linden S (2005) Serum-RANK-Ligand amplifies the effect of disease activity on radiographic progression. Ann Rheum Dis 62 (Suppl I):133

    Google Scholar 

  40. 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 osteoblastic cells. Bone 25:255–259

    Article  CAS  PubMed  Google Scholar 

  41. Brandstrom H, Jonsson KB, Vidal O, Ljunghall S, Ohlsson C, Ljunggren O (1998) Tumor necrosis factor-alpha and -beta upregulate the levels of osteoprotegerin mRNA in human osteosarcoma MG-63 cells. Biochem Biophys Res Commun 248:454–457

    Article  CAS  PubMed  Google Scholar 

  42. Chen RA, Goodman WG (2004) Role of calcium-sensing receptor in parathyroid gland physiology. Am J Physiol Renal Physiol 286:1005–1011

    Article  Google Scholar 

  43. Ebert R, Jovanovic M, Ulmer M, Schneider D, Meissner-Weigl J, Adamski J, Jakob F (2004) Down-regulation by nuclear factor kappaB of human 25-hydroxyvitamin D3 1 alpha-hydroxylase promoter. Mol Endocrinol 18:2440–2450

    Article  CAS  PubMed  Google Scholar 

  44. O’Brien EA, Williams JH, Marshall MJ (2001) Osteoprotegerin is produced when prostaglandin synthesis is inhibited causing osteoclasts to detach from the surface of mouse parietal bone and attach the endocranial membrane. Bone 28:208–214

    Article  PubMed  Google Scholar 

  45. Nagai M, Sato N (1999) Reciprocal gene expression of osteoclastogenesis inhibitory factor and osteoclast differentiation factor regulates osteoclast formation. Biochem Biophys Res Commun 257:719–723

    Article  CAS  PubMed  Google Scholar 

  46. Buzi F, Maccarinelli G, Guaragni B, Ruggeri F, Radetti G, Meini A, Mazzolari E, Cocchi D (2004) Serum osteoprotegerin and receptor activator of nuclear factors kB (RANKL) concentrations in normal children and in children with pubertal precocity, Turner’s syndrome and rheumatoid arthritis. Clin Endocrinol 60:87–91

    Article  CAS  Google Scholar 

  47. Bernstein CN, Sargent M, Leslie WD (2005) Serum osteoprotegerin is increased in Crohn’s disease: a population-based case control study. Inflamm Bowel Dis 11:325–330

    Article  PubMed  Google Scholar 

  48. Fabrega E, Orive A, Garcia-Suarez C, Garcia-Unzueta M, Antonio Amado J, Pons-Romero F (2005) Osteoprotegerin and RANKL in alcoholic liver cirrhosis. Liver Int 25:305–310

    Article  CAS  PubMed  Google Scholar 

  49. Grigorie D, Neacsu E, Marinescu M, Popa O (2003) Circulating osteoprotegerin and leptin levels in postmenopausal women with and without osteoporosis. Rom J Intern Med 41:409–415

    CAS  PubMed  Google Scholar 

  50. Mezquita-Raya P, de la Higuera M, Garcia DF, Alonso G, Ruiz-Requena ME, de Dios Luna J, Escobar-Jimenez F, Munoz-Torres M (2005) The contribution of serum osteoprotegerin to bone mass and vertebral fractures in postmenopausal women. Osteoporos Int 16:1368–1374

    Article  PubMed  Google Scholar 

  51. Tourinho TF, Stein A, Castro JA, Brenol JC (2005) Rheumatoid arthritis: evidence for bone loss in premenopausal women. J Rheumatol 32:1020–1025

    PubMed  Google Scholar 

  52. Barrera P, Boerbooms AM, Sauerwein RW, Demacker PN, van de Putte LB, van der Meer JW (1994) Interference of circulating azathioprine but not methotrexate or sulfasalazine with measurements of interleukin-6 bioactivity. Lymphokine Cytokine Res 13:155–159

    CAS  PubMed  Google Scholar 

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Acknowledgement

This work was supported by the Thuringian Ministry of Science, Research and Art (FKZ B307-01025).

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Authors and Affiliations

  1. Division of Rheumatology and Osteology, Department of Internal Medicine III, Friedrich Schiller University, Jena, Germany

    P. Oelzner, S. Franke, G. Lehmann, T. Eidner, A. Müller, G. Wolf & G. Hein

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  1. P. Oelzner
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  2. S. Franke
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  3. G. Lehmann
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  4. T. Eidner
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Correspondence to P. Oelzner.

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Oelzner, P., Franke, S., Lehmann, G. et al. Soluble receptor activator of NFkappa B-ligand and osteoprotegerin in rheumatoid arthritis - relationship with bone mineral density, disease activity and bone turnover. Clin Rheumatol 26, 2127–2135 (2007). https://doi.org/10.1007/s10067-007-0639-5

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