Best Practice & Research Clinical Rheumatology
Volume 20, Issue 5 , Pages 969-981 , October 2006

The role of mesenchymal cells in the pathophysiology of inflammatory arthritis

  • Lars-Henrik Meyer, MSc (Research Fellow)
    • ,
  • Lars Franssen, MSc (Research Fellow)
    • ,
  • Thomas Pap, MD (Professor of Experimental Medicine and Head)

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: +49 251 835 7798; Fax: +49 251 835 7462.

References 

  1. Smith RS, Smith TJ, Blieden TM, Phipps RP. Fibroblasts as sentinel cells. Synthesis of chemokines and regulation of inflammation. The American Journal of Pathology. 1997;151(2):317–322
  2. Takemura S, Klimiuk PA, Braun A, et al. T cell activation in rheumatoid synovium is B cell dependent. Journal of Immunology. 2001;167:4710–4718
  3. Seibl R, Birchler T, Loeliger S, et al. Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium. The American Journal of Pathology. 2003;162(4):1221–1227
  4. Pierer M, Rethage J, Seibl R, et al. Chemokine secretion of rheumatoid arthritis synovial fibroblasts stimulated by Toll-like receptor 2 ligands. Journal of Immunology. 2004;172(2):1256–1265
  5. Brentano F, Schorr O, Gay RE, et al. RNA released from necrotic synovial fluid cells activates rheumatoid arthritis synovial fibroblasts via Toll-like receptor 3. Arthritis and Rheumatism. 2005;52(9):2656–2665
  6. Haynes BF, Grover BJ, Whichard LP, et al. Synovial microenvironment-T cell interactions. Human T cells bind to fibroblast-like synovial cells in vitro. Arthritis and Rheumatism. 1988;31(8):947–955
  7. Salmon M, Scheel-Toellner D, Huissoon AP, et al. Inhibition of T cell apoptosis in the rheumatoid synovium. The Journal of Clinical Investigation. 1997;99:439–446
  8. Bombara M, Webb DL, Conrad P, et al. Cell contact between T cells and synovial fibroblasts causes induction of adhesion molecules and cytokines. Journal of Leukocyte Biology. 1993;54(5):399–406
  9. Lindhout E, van Eijk M, van Pel M, et al. Fibroblast-like synoviocytes from rheumatoid arthritis patients have intrinsic properties of follicular dendritic cells. Journal of Immunology. 1999;162:5949–5956
  10. Hamann J, Wishaupt JO, van Lier RA, et al. Expression of the activation antigen CD97 and its ligand CD55 in rheumatoid synovial tissue. Arthritis and Rheumatism. 1999;42:650–658
  11. Buckley CD, Pilling D, Lord JM, et al. Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation. Trends in Immunology. 2001;22(4):199–204
  12. Firestein GS, Zvaifler NJ. How important are T cells in chronic rheumatoid synovitis?: II. T cell-independent mechanisms from beginning to end. Arthritis and Rheumatism. 2002;46(2):298–308
  13. Pope RM, Perlman H. Rheumatoid arthritis. In:  Tsokas GC editors. Principles of Molecular Rheumatology. Totowa, New Jersey: Humana Press; 2000;p. 325–361
  14. Franz JK, Kolb SA, Hummel KM, et al. Interleukin-16 produced by synovial fibroblasts mediates chemoattraction to CD4+ T-cells in rheumatoid arthritis. European Journal of Immunology. 1998;28:2661–2671
  15. Harada S, Yamamura M, Okamoto H, et al. Production of interleukin-7 and interleukin-15 by fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis and Rheumatism. 1999;42(7):1508–1516
  16. Nanki T, Hayashida K, El-Gabalawy HS, et al. Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis synovium. Journal of Immunology. 2000;165(11):6590–6598
  17. Rollins BJ. Monocyte chemoattractant protein 1: a potential regulator of monocyte recruitment in inflammatory disease. Molecular Medicine Today. 1996;2(5):198–204
  18. Iwamoto T, Okamoto H, Iikuni N, et al. Monocyte chemoattractant protein-4 (MCP-4)/CCL13 is highly expressed in cartilage from patients with rheumatoid arthritis. Rheumatology (Oxford). 2006;45(4):421–424
  19. Sciaky D, Brazer W, Center DM, et al. Cultured human fibroblasts express constitutive IL-16 mRNA: cytokine induction of active IL-16 protein synthesis through a caspase-3-dependent mechanism. Journal of Immunology. 2000;164(7):3806–3814
  20. Pritchard J, Tsui S, Horst N, et al. Synovial fibroblasts from patients with rheumatoid arthritis, like fibroblasts from Graves' disease, express high levels of IL-16 when treated with Igs against insulin-like growth factor-1 receptor. Journal of Immunology. 2004;173(5):3564–3569
  21. Qu Z, Garcia CH, O'Rourke LM, et al. Local proliferation of fibroblast-like synoviocytes contributes to synovial hyperplasia. Results of proliferating cell nuclear antigen/cyclin, c-myc and nucleolar organizer region staining. Arthritis and Rheumatism. 1994;37(2):212–220
  22. Taniguchi K, Kohsaka H, Inoue N, et al. Induction of the p16INK4a senescence gene as a new therapeutic strategy for the treatment of rheumatoid arthritis. Nature Medicine. 1999;5(7):760–767
  23. Mor A, Abramson SB, Pillinger MH. The fibroblast-like synovial cell in rheumatoid arthritis: a key player in inflammation and joint destruction. Clinical Immunology. 2005;115(2):118–128
  24. Aicher WK, Heer AH, Trabandt A, et al. Overexpression of zinc-finger transcription factor Z-225/Egr-1 in synoviocytes from rheumatoid arthritis patients. Journal of Immunology. 1994;152(12):5940–5948
  25. Mountz JD, Hsu HC, Matsuki Y, Zhang HG. Apoptosis and rheumatoid arthritis: past, present, and future directions. Current Rheumatology Reports. 2001;3(1):70–78
  26. Perlman H, Georganas C, Pagliari LJ, et al. Bcl-2 expression in synovial fibroblasts is essential for maintaining mitochondrial homeostasis and cell viability. Journal of Immunology. 2000;164(10):5227–5235
  27. Liu H, Pope RM. The role of apoptosis in rheumatoid arthritis. Current Opinion in Pharmacology. 2003;3(3):317–322
  28. Wakisaka S, Suzuki N, Takeba Y, et al. Modulation by proinflammatory cytokines of Fas/Fas ligand-mediated apoptotic cell death of synovial cells in patients with rheumatoid arthritis (RA). Clinical and Experimental Immunology. 1998;114(1):119–128
  29. Kurowska M, Rudnicka W, Kontny E, et al. Fibroblast-like synoviocytes from rheumatoid arthritis patients express functional IL-15 receptor complex: endogenous IL-15 in autocrine fashion enhances cell proliferation and expression of Bcl-x(L) and Bcl-2. Journal of Immunology. 2002;169(4):1760–1767
  30. Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science. 1998;281:1305–1308
  31. Nakajima T, Aono H, Hasunuma T, et al. Apoptosis and functional Fas antigen in rheumatoid arthritis synoviocytes. Arthritis and Rheumatism. 1995;38(4):485–491
  32. Pap T, Muller-Ladner U, Gay RE, Gay S. Fibroblast biology. Role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis Research. 2000;2:361–367
  33. Hasunuma T, Kayagaki N, Asahara H, et al. Accumulation of soluble Fas in inflamed joints of patients with rheumatoid arthritis. Arthritis and Rheumatism. 1997;40(1):80–86
  34. Takemura Y, Fukuo K, Yasuda O, et al. Fas signaling induces Akt activation and upregulation of endothelial nitric oxide synthase expression. Hypertension. 2004;43(4):880–884
  35. Osaki M, Kase S, Adachi K, et al. Inhibition of the PI3K-Akt signaling pathway enhances the sensitivity of Fas-mediated apoptosis in human gastric carcinoma cell line, MKN-45. Journal of Cancer Research and Clinical Oncology. 2004;130(1):8–14
  36. Perlman H, Pagliari LJ, Liu H, et al. Rheumatoid arthritis synovial macrophages express the Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein and are refractory to Fas-mediated apoptosis. Arthritis and Rheumatism. 2001;44(1):21–30
  37. Catrina AI, Ulfgren AK, Lindblad S, et al. Low levels of apoptosis and high FLIP expression in early rheumatoid arthritis synovium. Annals of the Rheumatic Diseases. 2002;61(10):934–936
  38. Schedel J, Gay RE, Kuenzler P, et al. FLICE-inhibitory protein expression in synovial fibroblasts and at sites of cartilage and bone erosion in rheumatoid arthritis. Arthritis and Rheumatism. 2002;46(6):1512–1518
  39. Irmler M, Thome M, Hahne M, et al. Inhibition of death receptor signals by cellular FLIP. Nature. 1997;388(6638):190–195
  40. Palao G, Santiago B, Galindo M, et al. Down-regulation of FLIP sensitizes rheumatoid synovial fibroblasts to Fas-mediated apoptosis. Arthritis and Rheumatism. 2004;50(9):2803–2810
  41. Melchior F. SUMO–nonclassical ubiquitin. Annual Review of Cell and Developmental Biology. 2000;16:591–626
  42. Okura T, Gong L, Kamitani T, et al. Protection against Fas/APO-1- and tumor necrosis factor-mediated cell death by a novel protein, sentrin. Journal of Immunology. 1996;157:4277–4281
  43. Franz JK, Pap T, Hummel KM, et al. Expression of sentrin, a novel antiapoptotic molecule, at sites of synovial invasion in rheumatoid arthritis. Arthritis and Rheumatism. 2000;43:599–607
  44. Ghezzi P, Cerami A. Tumor necrosis factor as a pharmacological target. Molecular Biotechnology. 2005;31(3):239–244
  45. Reddy SAG, Huang JH, Liao WSL. Phosphatidylinositol 3-kinase as a mediator of TNF-induced NF-kappa B activation. Journal of Immunology. 2000;164(3):1355–1363
  46. Keffer J, Probert L, Cazlaris H, et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. The EMBO Journal. 1991;10(13):4025–4031
  47. Chu CQ, Field M, Feldmann M, Maini RN. Localization of tumour necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis. Arthritis and Rheumatism. 1991;34:1125–1132
  48. Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annual Review of Immunology. 1996;14:397–440
  49. Hsu H, Shu HB, Pan MG, et al. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell. 1996;84(2):299–308
  50. Madge LA, Pober JS. A phosphatidylinositol 3-kinase/Akt pathway, activated by tumor necrosis factor or interleukin-1, inhibits apoptosis but does not activate NFkappaB in human endothelial cells. The Journal of Biological Chemistry. 2000;275(20):15458–15465
  51. Ohshima S, Mima T, Sasai M, et al. Tumour necrosis factor alpha (TNFα) interferes with Fas-mediated apoptotic cell death on rheumatoid arthritis (RA) synovial cells: a possible mechanism ofrheumatoid synovial hyperplasia and a clinical benefit of anti-TNFα therapy for RA. Cytokine. 2000;12(3):281–288
  52. Drynda A, Quax PH, Neumann M, et al. Gene transfer of tissue inhibitor of metalloproteinases-3 reverses the inhibitory effects of TNFα on Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts. Journal of Immunology. 2005;174(10):6524–6531
  53. Sen M. Wnt signalling in rheumatoid arthritis. Rheumatology (Oxford). 2005;44(6):708–713
  54. Muller-Ladner U, Kriegsmann J, Franklin BN, et al. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. The American Journal of Pathology. 1996;149(5):1607–1615
  55. Ospelt C, Neidhart M, Gay RE, Gay S. Synovial activation in rheumatoid arthritis. Frontiers in Bioscience. 2004;9:2323–2334
  56. Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiological Reviews. 2003;83:835–870
  57. Stransky G, Vernon J, Aicher WK, et al. Virus-like particles in synovial fluids from patients with rheumatoid arthritis. British Journal of Rheumatology. 1993;32(12):1044–1048
  58. Franz JK, Pap T, Muller-Ladner U, et al. T cell-independent joint destruction. In:  Miossec P,  van den Berg WB,  Firestein GS editor. T cells in arthritis. Basel: Birkhäuser Verlag; 1998;p. 55–74
  59. el Gabalawy H, Wilkins J. Beta 1 (CD29) integrin expression in rheumatoid synovial membranes: an immunohistologic study of distribution patterns. The Journal of Rheumatology. 1993;20:231–237
  60. Muller-Ladner U, Elices MJ, Kriegsmann J, et al. Alternatively spliced CS-1 fibronectin isoform and its receptor VLA-4 in rheumatoid synovium demonstrated by in situ hybridization and immunohistochemistry. The Journal of Rheumatology. 1997;24:1873–1880
  61. Pirila L, Aho H, Roivainen A, et al. Identification of alpha6beta1 integrin positive cells in synovial lining layer as type B synoviocytes. The Journal of Rheumatology. 2001;28:478–484
  62. Rinaldi N, Schwarz EM, Weis D, et al. Increased expression of integrins on fibroblast-like synoviocytes from rheumatoid arthritis in vitro correlates with enhanced binding to extracellular matrix proteins. Annals of the Rheumatic Diseases. 1997;56:45–51
  63. Sarkissian M, Lafyatis R. Integrin engagement regulates proliferation and collagenase expression of rheumatoid synovial fibroblasts. Journal of Immunology. 1999;162:1772–1779
  64. Lin TH, Chen Q, Howe A, Juliano RL. Cell anchorage permits efficient signal transduction between ras and its downstream kinases. Journal of Biological Chemistry. 1997;272:8849–8852
  65. Inoue H, Yamashita A, Hakura A. Adhesion-dependency of serum-induced p42/44 MAP kinase activation is released by retroviral oncogenes. Virology. 1996;225:223–226
  66. Ravanti L, Heino J, Lopez-Otin C, Kahari VM. Induction of collagenase-3 (MMP-13) expression in human skin fibroblasts by three-dimensional collagen is mediated by p38 mitogen-activated protein kinase. Journal of Biological Chemistry. 1999;274:2446–2455
  67. Wang AZ, Wang JC, Fisher GW, Diamond HS. Interleukin-1beta-stimulated invasion of articular cartilage by rheumatoid synovial fibroblasts is inhibited by antibodies to specific integrin receptors and by collagenase inhibitors. Arthritis and Rheumatism. 1997;40:1298–1307
  68. Mulherin D, Fitzgerald O, Bresnihan B. Clinical improvement and radiological deterioration in rheumatoid arthritis: evidence that the pathogenesis of synovial inflammation and articular erosion may differ. British Journal of Rheumatology. 1996;35(12):1263–1268
  69. Kraan MC, Versendaal H, Jonker M, et al. Asymptomatic synovitis precedes clinically manifest arthritis. Arthritis and Rheumatism. 1998;41(8):1481–1488
  70. Brown PD. Ongoing trials with matrix metalloproteinase inhibitors. Expert Opinion on Investigational Drugs. 2000;9:2167–2177
  71. Muller-Ladner U, Gay RE, Gay S. Cysteine proteinases in arthritis and inflammation. Perspect Drug Discovery Design. 1996;6:87–98
  72. Parks WC, Mecham RP. Matrix metalloproteinases. San Diego: Academic Press; 1998;
  73. Nagase H. Activation mechanisms of matrix metalloproteinases. Biological Chemistry. 1997;378:151–160
  74. Pap T, Shigeyama Y, Kuchen S, et al. Differential expression of membrane-type matrix metalloproteinases (MT-MMPs) in rheumatoid arthritis (RA). Arthritis and Rheumatism. 2000;43:1226–1232
  75. Kinne RW, Boehm S, Iftner T, et al. Synovial fibroblast-like cells strongly express jun-B and C-fos proto-oncogenes in rheumatoid- and osteoarthritis. Scandinavian Journal of Rheumatology Supplement. 1995;101:121–125
  76. Asahara H, Fujisawa K, Kobata T, et al. Direct evidence of high DNA-binding activity of transcription factor AP-1 in rheumatoid arthritis synovium. Arthritis and Rheumatism. 1997;40:912–918
  77. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423:356–361
  78. Han Z, Boyle DL, Manning AM, Firestein GS. AP-1 and NF-kappaB regulation in rheumatoid arthritis and murine collagen-induced arthritis. Autoimmunity. 1998;28(4):197–208
  79. Han Z, Boyle DL, Chang L, et al. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. The Journal of Clinical Investigation. 2001;108(1):73–81
  80. Bond M, Fabunmi RP, Baker AH, Newby AC. Synergistic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: an absolute requirement for transcription factor NF-kappa B. FEBS Letters. 1998;435(1):29–34
  81. Bond M, Baker AH, Newby AC. Nuclear factor kappaB activity is essential for matrix metalloproteinase-1 and -3 upregulation in rabbit dermal fibroblasts. Biochemical and Biophysical Research Communications. 1999;264(2):561–567
  82. Bondeson J, Brennan F, Foxwell B, Feldmann M. Effective adenoviral transfer of IkappaBalpha into human fibroblasts and chondrosarcoma cells reveals that the induction of matrix metalloproteinases and proinflammatory cytokines is nuclear factor-kappaB dependent. The Journal of Rheumatology. 2000;27(9):2078–2089
  83. Reunanen N, Li S, Ahonen M, et al. Activation of p38α MAPK enhances collagenase-1 (matrix metalloproteinase (MMP)-1) and stromelysin-1 (MMP-3) expression by mRNA stabilization. Journal of Biological Chemistry. 2002;277(35):32360–32368
  84. Kotlyarov A, Gaestel M. Is MK2 (mitogen-activated protein kinase-activated protein kinase 2) the key for understanding post-transcriptional regulation of gene expression?. Biochemical Society Transactions. 2002;30:959–963
  85. Vincenti MP, Coon CI, Lee O, Brinckerhoff CE. Regulation of collagenase gene expression by IL-1 beta requires transcriptional and post-transcriptional mechanisms. Nucleic Acids Research. 1994;22(22):4818–4827
  86. Delany AM, Brinckerhoff CE. Post-transcriptional regulation of collagenase and stromelysin gene expression by epidermal growth factor and dexamethasone in cultured human fibroblasts. Journal of Cellular Biochemistry. 1992;50(4):400–410
  87. Saarialho-Kere UK, Chang ES, Welgus HG, Parks WC. Expression of interstitial collagenase, 92-kDa gelatinase, and tissue inhibitor of metalloproteinases-1 in granuloma annulare and necrobiosis lipoidica diabeticorum. Journal of Investigative Dermatology. 1993;100(3):335–342
  88. Brinckerhoff CE, Plucinska IM, Sheldon LA, O'Connor GT. Half-life of synovial cell collagenase mRNA is modulated by phorbol myristate acetate but not by all-trans-retinoic acid or dexamethasone. Biochemistry. 1986;25(21):6378–6384
  89. Pei D, Weiss SJ. Furin-dependent intracellular activation of human stromelysin-3 zymogen. Nature. 1995;375:244–247
  90. Gomez DE, Alonso DF, Yoshijji H, Thorgeirsson UP. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. European Journal of Cell Biology. 1997;74:111–122
  91. Brew K, Dinakarpandian D, Nagase H. Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochimica et Biophysica Acta. 2000;1477:267–283
  92. Jackson CJ, Arkell J, Nguyen M. Rheumatoid synovial endothelial cells secrete decreased levels of tissue inhibitor of MMP (TIMP1). Annals of the Rheumatic Diseases. 1998;57(3):158–161
  93. Su S, Grover J, Roughley PJ, et al. Expression of the tissue inhibitors of metalloproteinases (TIMP) gene family in normal and osteoarthritic joints. Rheumatoloy International. 1999;18:183–191
  94. Kraan MC, Reece RJ, Barg EC, et al. Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis. Findings in a prospective, randomized, double-blind, parallel-design clinical trial in thirty-nine patients at two centers. Arthritis and Rheumatism. 2000;43:1820–1830
  95. Pap T, Muller-Ladner U, Gay RE, Gay S. Gene therapy in rheumatoid arthritis: how to target joint destruction?. Arthritis Research. 1999;1:5–9
  96. Greenwald RA, Golub LM, Ramamurthy NS, et al. In vitro sensitivity of the three mammalian collagenases to tetracycline inhibition: relationship to bone and cartilage degradation. Bone. 1998;22:33–38
  97. Greenwald RA. Thirty-six years in the clinic without an MMP inhibitor. What hath collagenase wrought?. Annals of the New York Academy of Sciences. 1999;878:413–419
  98. Joosten LA, Helsen MM, Saxne T, et al. IL-1 alpha beta blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNFα blockade only ameliorates joint inflammation. Journal of Immunology. 1999;163(9):5049–5055

PII: S1521-6942(06)00077-5

doi: 10.1016/j.berh.2006.06.005

Best Practice & Research Clinical Rheumatology
Volume 20, Issue 5 , Pages 969-981 , October 2006

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