• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of annrheumdAnnals of the Rheumatic DiseasesCurrent TOCInstructions for authors
Ann Rheum Dis. Dec 2002; 61(12): 1047–1054.
PMCID: PMC1753975

Receptor activator NF-κB ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis

Abstract

Objectives: To compare receptor activator of NF-κB ligand (RANKL) production in the synovial tissue from patients with active rheumatoid arthritis (RA), inactive RA, spondyloarthropathies (SpA), osteoarthritis, and from normal subjects. In addition, to establish the cell lineages expressing RANKL in these tissues.

Methods: Immunohistological analysis of frozen synovial tissue biopsy specimens was performed using a monoclonal antibody (mAb) to detect RANKL. Sections were evaluated by computer assisted image analysis and semiquantitative analysis to compare RANKL expression between groups. Dual and sequential labelling with mAb RANKL and cell lineage specific monoclonal antibodies were used to determine the types of cells expressing RANKL.

Results: Higher levels of RANKL were expressed in tissues from patients with active RA and SpA than in tissues from patients with inactive RA, osteoarthritis, and from normal subjects. RANKL protein was associated with CD3 antigen-positive lymphocytes and some macrophages. RANKL was predominantly associated with activated, memory T cells (CD45Ro positive cells) in patients with active RA and spondyloarthropathy (SpA).

Conclusions: The highest levels of RANKL were detected in patients with RA with active synovitis and in some patients with SpA. An increase in RANKL in the inflamed joint of patients with RA, produced by infiltrating activated T cells and macrophages, is likely to be an important cause of joint erosions in RA.

Full Text

The Full Text of this article is available as a PDF (282K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • van Zeben D, Hazes JM, Zwinderman AH, Vandenbroucke JP, Breedveld FC. Factors predicting outcome of rheumatoid arthritis: results of a followup study. J Rheumatol. 1993 Aug;20(8):1288–1296. [PubMed]
  • Woolley DE, Crossley MJ, Evanson JM. Collagenase at sites of cartilage erosion in the rheumatoid joint. Arthritis Rheum. 1977 Jul-Aug;20(6):1231–1239. [PubMed]
  • Trabandt A, Gay RE, Fassbender HG, Gay S. Cathepsin B in synovial cells at the site of joint destruction in rheumatoid arthritis. Arthritis Rheum. 1991 Nov;34(11):1444–1451. [PubMed]
  • Tetlow LC, Woolley DE. Mast cells, cytokines, and metalloproteinases at the rheumatoid lesion: dual immunolocalisation studies. Ann Rheum Dis. 1995 Nov;54(11):896–903. [PMC free article] [PubMed]
  • Gravallese EM, Manning C, Tsay A, Naito A, Pan C, Amento E, Goldring SR. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum. 2000 Feb;43(2):250–258. [PubMed]
  • Takayanagi H, Iizuka H, Juji T, Nakagawa T, Yamamoto A, Miyazaki T, Koshihara Y, Oda H, Nakamura K, Tanaka S. Involvement of receptor activator of nuclear factor kappaB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum. 2000 Feb;43(2):259–269. [PubMed]
  • Romas E, Bakharevski O, Hards DK, Kartsogiannis V, Quinn JM, Ryan PF, Martin TJ, Gillespie MT. Expression of osteoclast differentiation factor at sites of bone erosion in collagen-induced arthritis. Arthritis Rheum. 2000 Apr;43(4):821–826. [PubMed]
  • Haynes DR, Crotti TN, Loric M, Bain GI, Atkins GJ, Findlay DM. Osteoprotegerin and receptor activator of nuclear factor kappaB ligand (RANKL) regulate osteoclast formation by cells in the human rheumatoid arthritic joint. Rheumatology (Oxford) 2001 Jun;40(6):623–630. [PubMed]
  • Chu CQ, Field M, Allard S, Abney E, Feldmann M, Maini RN. Detection of cytokines at the cartilage/pannus junction in patients with rheumatoid arthritis: implications for the role of cytokines in cartilage destruction and repair. Br J Rheumatol. 1992 Oct;31(10):653–661. [PubMed]
  • Deleuran BW, Chu CQ, Field M, Brennan FM, Katsikis P, Feldmann M, Maini RN. Localization of interleukin-1 alpha, type 1 interleukin-1 receptor and interleukin-1 receptor antagonist in the synovial membrane and cartilage/pannus junction in rheumatoid arthritis. Br J Rheumatol. 1992 Dec;31(12):801–809. [PubMed]
  • Chu CQ, Field M, Feldmann M, Maini RN. Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis. Arthritis Rheum. 1991 Sep;34(9):1125–1132. [PubMed]
  • Kotake S, Sato K, Kim KJ, Takahashi N, Udagawa N, Nakamura I, Yamaguchi A, Kishimoto T, Suda T, Kashiwazaki S. 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. 1996 Jan;11(1):88–95. [PubMed]
  • Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S, Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, et al. Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med. 2000 Jan 17;191(2):275–286. [PMC free article] [PubMed]
  • Nakashima T, Kobayashi Y, Yamasaki S, Kawakami A, Eguchi K, Sasaki H, Sakai H. Protein expression and functional difference of membrane-bound and soluble receptor activator of NF-kappaB ligand: modulation of the expression by osteotropic factors and cytokines. Biochem Biophys Res Commun. 2000 Sep 7;275(3):768–775. [PubMed]
  • Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3597–3602. [PMC free article] [PubMed]
  • Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999 Jan 28;397(6717):315–323. [PubMed]
  • Quinn JM, Horwood NJ, Elliott J, Gillespie MT, Martin TJ. Fibroblastic stromal cells express receptor activator of NF-kappa B ligand and support osteoclast differentiation. J Bone Miner Res. 2000 Aug;15(8):1459–1466. [PubMed]
  • Horwood NJ, Kartsogiannis V, Quinn JM, Romas E, Martin TJ, Gillespie MT. Activated T lymphocytes support osteoclast formation in vitro. Biochem Biophys Res Commun. 1999 Nov;265(1):144–150. [PubMed]
  • Kotake S, Udagawa N, Hakoda M, Mogi M, Yano K, Tsuda E, Takahashi K, Furuya T, Ishiyama S, Kim KJ, et al. Activated human T cells directly induce osteoclastogenesis from human monocytes: possible role of T cells in bone destruction in rheumatoid arthritis patients. Arthritis Rheum. 2001 May;44(5):1003–1012. [PubMed]
  • Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998 Apr 17;93(2):165–176. [PubMed]
  • Burgess TL, Qian Y, Kaufman S, Ring BD, Van G, Capparelli C, Kelley M, Hsu H, Boyle WJ, Dunstan CR, et al. The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts. J Cell Biol. 1999 May 3;145(3):527–538. [PMC free article] [PubMed]
  • Wong BR, Josien R, Lee SY, Sauter B, Li HL, Steinman RM, Choi Y. TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J Exp Med. 1997 Dec 15;186(12):2075–2080. [PMC free article] [PubMed]
  • Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 1997 Nov 13;390(6656):175–179. [PubMed]
  • Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett FS, 3rd, Frankel WN, et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J Biol Chem. 1997 Oct 3;272(40):25190–25194. [PubMed]
  • Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997 Apr 18;89(2):309–319. [PubMed]
  • Yasuda H, Shima N, Nakagawa N, Mochizuki SI, Yano K, Fujise N, Sato Y, Goto M, Yamaguchi K, Kuriyama M, et al. Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology. 1998 Mar;139(3):1329–1337. [PubMed]
  • Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, et al. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998 May 1;12(9):1260–1268. [PMC free article] [PubMed]
  • Mizuno A, Amizuka N, Irie K, Murakami A, Fujise N, Kanno T, Sato Y, Nakagawa N, Yasuda H, Mochizuki S, et al. Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun. 1998 Jun 29;247(3):610–615. [PubMed]
  • Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. [PubMed]
  • Dougados M, van der Linden S, Juhlin R, Huitfeldt B, Amor B, Calin A, Cats A, Dijkmans B, Olivieri I, Pasero G, et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum. 1991 Oct;34(10):1218–1227. [PubMed]
  • Gladman DD, Farewell VT. Progression in psoriatic arthritis: role of time varying clinical indicators. J Rheumatol. 1999 Nov;26(11):2409–2413. [PubMed]
  • Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, Christy W, Cooke TD, Greenwald R, Hochberg M, et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum. 1986 Aug;29(8):1039–1049. [PubMed]
  • Smith MD, Chandran G, Youssef PP, Darby T, Ahern MJ. Day case knee arthroscopy under regional anaesthesia, performed by rheumatologists. Aust N Z J Med. 1996 Feb;26(1):108–109. [PubMed]
  • Smith MD, O'Donnell J, Highton J, Palmer DG, Rozenbilds M, Roberts-Thomson PJ. Immunohistochemical analysis of synovial membranes from inflammatory and non-inflammatory arthritides: scarcity of CD5 positive B cells and IL2 receptor bearing T cells. Pathology. 1992 Jan;24(1):19–26. [PubMed]
  • Kraan MC, Haringman JJ, Ahern MJ, Breedveld FC, Smith MD, Tak PP. Quantification of the cell infiltrate in synovial tissue by digital image analysis. Rheumatology (Oxford) 2000 Jan;39(1):43–49. [PubMed]
  • Tak PP, van der Lubbe PA, Cauli A, Daha MR, Smeets TJ, Kluin PM, Meinders AE, Yanni G, Panayi GS, Breedveld FC. Reduction of synovial inflammation after anti-CD4 monoclonal antibody treatment in early rheumatoid arthritis. Arthritis Rheum. 1995 Oct;38(10):1457–1465. [PubMed]
  • Parker A, Smith MD. Immunohistochemical detection of cytokines and cell adhesion molecules in the synovial membrane. Methods Find Exp Clin Pharmacol. 1999 Jun;21(5):311–319. [PubMed]
  • Wikaningrum R, Highton J, Parker A, Coleman M, Hessian PA, Roberts-Thompson PJ, Ahern MJ, Smith MD. Pathogenic mechanisms in the rheumatoid nodule: comparison of proinflammatory cytokine production and cell adhesion molecule expression in rheumatoid nodules and synovial membranes from the same patient. Arthritis Rheum. 1998 Oct;41(10):1783–1797. [PubMed]
  • Youssef PP, Haynes DR, Triantafillou S, Parker A, Gamble JR, Roberts-Thomson PJ, Ahern MJ, Smith MD. Effects of pulse methylprednisolone on inflammatory mediators in peripheral blood, synovial fluid, and synovial membrane in rheumatoid arthritis. Arthritis Rheum. 1997 Aug;40(8):1400–1408. [PubMed]
  • Youssef PP, Triantafillou S, Parker A, Coleman M, Roberts-Thomson PJ, Ahern MJ, Smith MD. Variability in cytokine and cell adhesion molecule staining in arthroscopic synovial biopsies: quantification using color video image analysis. J Rheumatol. 1997 Dec;24(12):2291–2298. [PubMed]
  • Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, Capparelli C, Li J, Elliott R, McCabe S, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. 1999 Nov 18;402(6759):304–309. [PubMed]
  • Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, Saito S, Inoue K, Kamatani N, Gillespie MT, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999 May;103(9):1345–1352. [PMC free article] [PubMed]
  • Haynes DR, Crotti TN, Potter AE, Loric M, Atkins GJ, Howie DW, Findlay DM. The osteoclastogenic molecules RANKL and RANK are associated with periprosthetic osteolysis. J Bone Joint Surg Br. 2001 Aug;83(6):902–911. [PubMed]
  • Fujikawa Y, Sabokbar A, Neale S, Athanasou NA. Human osteoclast formation and bone resorption by monocytes and synovial macrophages in rheumatoid arthritis. Ann Rheum Dis. 1996 Nov;55(11):816–822. [PMC free article] [PubMed]
  • Itonaga I, Fujikawa Y, Sabokbar A, Murray DW, Athanasou NA. Rheumatoid arthritis synovial macrophage-osteoclast differentiation is osteoprotegerin ligand-dependent. J Pathol. 2000 Sep;192(1):97–104. [PubMed]
  • Sakkas LI, Scanzello C, Johanson N, Burkholder J, Mitra A, Salgame P, Katsetos CD, Platsoucas CD. T cells and T-cell cytokine transcripts in the synovial membrane in patients with osteoarthritis. Clin Diagn Lab Immunol. 1998 Jul;5(4):430–437. [PMC free article] [PubMed]
  • Smith MD, Kraan MC, Slavotinek J, Au V, Weedon H, Parker A, Coleman M, Roberts-Thomson PJ, Ahern MJ. Treatment-induced remission in rheumatoid arthritis patients is characterized by a reduction in macrophage content of synovial biopsies. Rheumatology (Oxford) 2001 Apr;40(4):367–374. [PubMed]
  • Manabe N, Kawaguchi H, Chikuda H, Miyaura C, Inada M, Nagai R, Nabeshima Y, Nakamura K, Sinclair AM, Scheuermann RH, et al. Connection between B lymphocyte and osteoclast differentiation pathways. J Immunol. 2001 Sep 1;167(5):2625–2631. [PubMed]

Figures and Tables

Figure 1
RANKL detected with mAb 626/immunoperoxidase and AEC (red), in synovial tissue from a patient with RA with (A) active disease and (B) inactive disease, (C) a patient with SpA, and (D) a patient with OA. (E) to (H) identify cell lineages expressing RANKL ...
Figure 2
Panels (A), (C), (E), (G) demonstrate RANKL expression, detected with mAb 626/ immunoperoxidase and AEC (red), in synovial tissue from a patient with RA with active disease (A), inactive disease (C), SpA (E), and from a normal subject (G). Panels (B), ...

Articles from Annals of the Rheumatic Diseases are provided here courtesy of BMJ Group

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...