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Osteoprotegerin and the receptor activator of NF-kappa B ligand in the serum and synovial fluid. A comparison of patients with longstanding rheumatoid arthritis and osteoarthritis

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Abstract

We examined OPG and soluble RANKL in the serum (sOPG, sRANKL) and synovial fluid (synOPG, synRANKL) in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). OPG and RANKL were measured in 85 patients (44 with RA, 41 patients with OA) in serum and synovial fluid as well. For measuring of OPG and RANKL ELISA tests were used. The results of OPG and RANKL were compared with clinical and radiological scores. We found a negative correlation for OPG and RANKL in synovial fluids: not only for the whole group of patients (P< 0.003, r=−0.32), but also for the subgroups (RA: P<0.04, r=−0.28, OA: P<0.002, r=−0.54). SRANKL and synRANKL were positively correlated in the whole group (P<0.01, r=0.25) and in the OA group (P<0.02, r=0.35); the RA group was showing a trend (P<0.063, r=0.24), however. Serum OPG was lower in RA, synOPG higher in OA. The difference between the two patient groups was only significant for synOPG (P<0.03, r=0.056), but not for sOPG (P<0.09, r=0.19), sRANKL (P<0.43, r=0.85) or synRANKL (P<0.11, r=0.22). The synOPG:synRANKL ratio was significantly correlated with the Larsen score (P<0.004, r=0.38). Synovial OPG is significantly decreased in rheumatoid joints, whereby synovial RANKL is increased. Lower synOPG could reflect a lower protective effect on bone, thus leading to an earlier and more pronounced bone destruction in RA. However, the effect of different mediators for joint destruction in RA and OA seems not to be important to the pathophysiological changes in the joints. The upregulation of serum OPG might be the result of the inflammation; in contrast, an upregulation of RANKL could not be found in the serum of patients with RA and OA.

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References

  1. Pincus T, Callahan LF, Sale WG, Brooks AL, Payne LE, Vaughn WK (1984) Severe functional declines, work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine years. Arthritis Rheum 27:864–872

    CAS  PubMed  Google Scholar 

  2. Pincus T, Marcum SB, Callahan LF (1992) Longterm drug therapy for rheumatoid arthritis in seven rheumatology private practices: II. Second line drugs and prednisone. J Rheumatol 19:1885–1894

    CAS  PubMed  Google Scholar 

  3. Scott DL, Symmons DPM, Coulton BL, Popert AJ (1987) Long- term outcome of treating rheumatoid arthritis: results after 20 years. Lancet 1(8542):1108–1111

    Article  CAS  PubMed  Google Scholar 

  4. Sherrer YS, Bloch DA, Mitchell DM, Young DY, Fries JF (1986) The development of disability in rheumatoid arthritis. Arthritis Rheum 29:494–500

    CAS  PubMed  Google Scholar 

  5. Pincus T, Callahan LF (1986) Taking mortality in rheumatoid arthritis seriously—predictive markers, socioeconomic status and comorbidity. J Rheumatol 13:841–845

    CAS  PubMed  Google Scholar 

  6. Mulherin D, Fitzgerald O, Bresnihan B (1996) Clinical improvement and radiological deterioration in rheumatoid arthritis: evidence that the pathogenesis of synovial inflammation and articular erosion may differ. Br J Rheumatol 35:1263–1268

    Article  CAS  PubMed  Google Scholar 

  7. Palmer DG (1995) The anatomy of the rheumatoid lesion. Br Med Bull 51:286–295

    CAS  PubMed  Google Scholar 

  8. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Boyle WJ (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319

    Article  CAS  PubMed  Google Scholar 

  9. Itonaga I, Fujikawa Y, Sabokar A, Murray DW, Athanasou NA (2000) Rheumatoid arthritis synovial macrophage–osteoclast differentiation is osteoprotegerin ligand-dependent. J Pathol 192:97–104

    Article  CAS  PubMed  Google Scholar 

  10. Burgess TL, Qian Y, Kaufman S, Ring BD, Van G, Capparelli C, Kelley M, Hsu H, Boyle WJ, Dunstan CR, Hu S, Lacey DL (1999) The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts. J Cell Biol 145:527–538

    Article  CAS  PubMed  Google Scholar 

  11. Fuller K, Wong B, Fox S, Choi Y, Chambers TJ (1988) TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med 188: 997–1001

    Article  Google Scholar 

  12. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397:315–323

    Article  CAS  PubMed  Google Scholar 

  13. Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett FS III, Frankel WN, Lee SY, Choi Y (1997)TRANCE is a novel ligand of the tumor necrosis factor receptor family that activated c-jun N-terminal kinase in T-cells. J Biol Chem 272:25190–25194

    Article  CAS  PubMed  Google Scholar 

  14. 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 an adjuvant arthritis through osteoprotegerin ligand. Nature 402:304–309

    Article  CAS  PubMed  Google Scholar 

  15. Lum L, Wong BR, Josien R, Becherer JD, Erdjument-Bromage H, Schlondorff J, Tempst P, Choi Y, Blobel CP (1999) Evidence for a role of a tumor necrosis factor alpha converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dentritic cell survival. J Biol Chem 274:13613–13618

    Article  CAS  PubMed  Google Scholar 

  16. Fata JE, Kong YY, Li J, Sasaki T, Irie-Sasaki J, Moorehead RA, Elliott R, Scully S, Voura EB, Lacey DL, Boyle WJ, Khokha R, Penninger JM (2000) The osteoclast sifferentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103:41–50

    Article  CAS  PubMed  Google Scholar 

  17. Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, Tan HL, Elliott G, Kelley MJ, Sarosi I, Wang L, Xia XZ, Elliott R, Chiu L, Black T, Scully S, Capparelli C, Morony S, Shimamoto G, Bass MB, Boyle WJ (1999) Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. P Natl Acad Sci USA 96:3540–3545

    Article  CAS  Google Scholar 

  18. Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176

    Article  CAS  PubMed  Google Scholar 

  19. Hofbauer LC, Heufelder AC (2001) Role of receptor activator of nuclear factor -κB ligand and osteoprotegerin in bone cell biology. J Mol Med 79:243–253

    Article  CAS  PubMed  Google Scholar 

  20. Takayanagi H, Iizuka H, Juji T, Nakagawa T, Yamamoto A, Miyazaki T, Koshihara Y, Oda H, Nakamura K, Tanaka S (2004) Involvement of receptor activator of nuclear factor -κB ligand osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum 43:259–269

    Article  Google Scholar 

  21. Bolon B, Campagnuolo G, Hu Yl, Duryeda D, Feige U (2000) Arthritis patterns in rats with adjuvant-induced arthritis define distinct mechanisms of joint protection for IL-1ra, sTNF RI and OPG. Ann Rheum Dis 59(Suppl 1):355

    Google Scholar 

  22. Skoumal M, Kolarz G, Woloszczuk W, Hawa G, Klingler A (2004) Serumosteoprotegerin but not receptor activator of NF-kappa B ligand correlates with the Larsen score in rheumatoid arthritis. Ann Rheum Dis 63:216–217

    Article  CAS  PubMed  Google Scholar 

  23. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324

    CAS  PubMed  Google Scholar 

  24. Ritchie DM, Boyle JA, McInnes JM, Jasani MK, Dalakos TG, Grieveson P (1968) Clinical studies with an articular index for the assesments of joint tenderness in patients with rheumatoid arthritis. Q J Med 147:393–406

    Google Scholar 

  25. Smolen JS, Breedveld FC, Eberl G (1995) Validity and reliability of the twenty-eight-joint count for the assessment of rheumatoid arthritis. Arthritis Rheum 38:38–43

    CAS  Google Scholar 

  26. Larsen A, Dale K, Eek M (1976) Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films. Acta Radiol Diagn 18:481–491

    Google Scholar 

  27. Altmann RD, Hochberg M, Murphy WA, Wolfe FJ, Lequesne M (1995) Atlas of individual radiographic features in osteoarthritis. Osteoarthr Cartilage 3:3–70

    Google Scholar 

  28. Steinbrocker O, Traeger CH, Battermann RC (1949) Therapeutic criteria in rheumatoid arthritis. J Am Med Assoc 140:659

    Google Scholar 

  29. Kudlacek S, Schneider P, Pietschmann P, Woloszczuk W, Willvonseder R (2001) The effect of age on serum levels of osteoprotegerin. J Bone Miner Res 16 (Suppl 1)

  30. Hawa G, Brinskelle-Schmal N, Glatz K, Maitzen S, Woloszczuk W (2003) Immunoassay for Soluble RANKL (Receptor Activator of NF-κB Ligand) in Serum. Clin Lab 49:461-463

    CAS  Google Scholar 

  31. Li J, Sarosi I, Xan X-Q, Morony S, Capparelli C, Tan H-L, Mc Cabe S (1997) RANK is the intrinsinc hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. P Natl Acad Sci USA 97(4):1566–1571

    Article  Google Scholar 

  32. Mizuno A, Amizuka N, Irie K, Murakami A, Fujise N, Kanno T, Sato Y, Nakagawa N, Yasuda H, Mochizuki S, Gomibuchi T, Yano K, Shima N, Washida N, Tsuda E, Morinaga T, Higashio K, Ozawa H (1998) Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun 247:610–615

    Article  CAS  PubMed  Google Scholar 

  33. Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS (1998) Osteoprotegerin deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12:1260–1268

    CAS  PubMed  Google Scholar 

  34. 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 43:259–269

    Article  PubMed  Google Scholar 

  35. Collin- Osdoby P, Rothe L, Anderson F, Nelson M, Maloney W, Osdoby P (2001) Receptor activator of NF-kappa B and osteoprotegerin expression by human microvascular endothelial cells, regulation by inflammatory cytokines, and role in human osteoclastogenesis. J Biol Chem 276:20659–20672

    Article  CAS  PubMed  Google Scholar 

  36. Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, Saito S, Inoue K, Kamatani N, Gillespie MT, Martin TJ, Suda T (1999) IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 103:1345–1352

    CAS  PubMed  Google Scholar 

  37. Holstead Jones D, Kong Y-Y, Penninger JM (2002) Role of RANKL and RANK in bone loss and arthritis. Ann Rheum Dis 61(Suppl II):ii32–ii39

    PubMed  Google Scholar 

  38. Kolarz G, Schödl CH, Skoumal M, Woloszczuk W, Wottawa A (2003) Osteoprotegerin serum levels in rheumatoid arthritis. J Mineralstoffwechsel 3:10–12

    Google Scholar 

  39. Haynes DR, Crotti TN, Loric M, Bain GI, Atkins GJ, Findlay DM (2001) Osteoprotegerin and receptor activator of nuclear factor -κB ligand (RANKL) regulate osteoclast formation by cells in the human rheumatoid arthritic joint. Rheumatology 40:623–630

    Article  CAS  PubMed  Google Scholar 

  40. Kong YY, Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E (1999) Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. P Natl Acad Sci USA 96: 3540–3545

    Article  CAS  Google Scholar 

  41. Komuro H, Olee T, Kuhn K, Quach J, Brinson DC, Shikhman A, Valbracht J, Creighton-Achermann L, Lotz M (2001) The osteoprotegerin/receptor activator of nuclear factor kappa B/receptor activator of nuclear factor kappa B ligand system in cartilage. Arthritis Rheum 44:2768–2776

    Article  CAS  PubMed  Google Scholar 

  42. Crotti TN, Smith MD, Weedon H, Ahern MJ, Findlay DM, Kraan M, Tak PP, Haynes DR (2002) Receptor activator NF-kappa B ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondylarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis. Ann Rheum Dis 61:1047–1054

    Article  CAS  PubMed  Google Scholar 

  43. Haynes DR, Barg E, Crotti TN, Holding C, Weedon H, Atkins GJ, Zannetino A, Ahern MJ, Coleman M, Roberts-Thomson PJ, Kraan M, Tak PP, Smith MD (2003) Osteoprotegerin expression in synovial tissue from patients with rheumatoid arthritis, spondylarthropathies and osteoarthritis and normal controls. Rheumatology 42:123–34

    Article  CAS  PubMed  Google Scholar 

  44. Schett G, Redlich K, Smolen JS (2003) The role of Osteoprotegerin in arthritis. Arthritis Res Ther 5:239–245

    Article  CAS  PubMed  Google Scholar 

  45. Ziolkowska M, Kurowska M, Radzikowska A, Luszczykiewicz G, Wieland P, Dziewczopolski W, Filipowicz-Sosnowska A, Pazdur J, Szechinski 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(7):1744–1753

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institut für Rheumatologie der Kurstadt Baden in Kooperation mit der Donauuniversität Krems, Austria

    M. Skoumal, G. Kolarz & G. Haberhauer

  2. Rheumasonderkrankenanstalt der SVA der gewerblichen Wirtschaft, Adolfine Malchergasse 1, 2500, Baden, Austria

    M. Skoumal

  3. L. Boltzmann Institut für experimentelle Endokrinologie, Wien, Austria

    W. Woloszczuk

  4. Biomedica Medizinprodukte GmbH & CO KG, Austria

    G. Hawa

  5. Theoretical Surgery Unit, Department of General and Transplant Surgery, University Hospital, Innsbruck, Austria

    A. Klingler

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  1. M. Skoumal
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  2. G. Kolarz
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  3. G. Haberhauer
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  4. W. Woloszczuk
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  5. G. Hawa
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  6. A. Klingler
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Correspondence to M. Skoumal.

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Skoumal, M., Kolarz, G., Haberhauer, G. et al. Osteoprotegerin and the receptor activator of NF-kappa B ligand in the serum and synovial fluid. A comparison of patients with longstanding rheumatoid arthritis and osteoarthritis. Rheumatol Int 26, 63–69 (2005). https://doi.org/10.1007/s00296-004-0579-1

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  • DOI: https://doi.org/10.1007/s00296-004-0579-1

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