Abstract
Chronic arthritis is characterized by a persistent joint inflammation and concomitant joint destruction. Although the joint swelling is a major clinical problem, destruction of bone and cartilage may occur uncoupled to inflammation and it is of utmost importance to fully understand the elements of the destructive process. TNF and IL-1 are considered master cytokines in the process of human RA, with a claimed cascade of TNF inducing most of the IL-1 production. Studies in experimental models revealed that TNF is indeed a pivotal cytokine in joint swelling, yet IL-1 is the dominant cartilage destructive cytokine and its production may occur independent of TNF. This was found with anti-TNF/IL-1 neutralizing antibodies and the observations were recently backed up with similar data in arthritis models in TNF and IL-1 knockout mice. Apart from the absolute level of IL-1, the destructive potential of an arthritis is determined by the balance with regulatory cytokines and anabolic growth factors. IL-4, IL-6, and IL-10 can promote inflammation and tissue fibrosis, yet cartilage destruction is found to be greatly reduced by these cytokines, linked to a range of pathways which can reduce the IL-1 impact on the articular cartilage. Finally, the presence of anabolic growth factors in the inflamed synovium may have a major impact on net destruction. Endogenous transforming growth factor-β (TGF-β) is found in inflamed synovia, but local coadministration of TGF-β further enhanced the degree of synovitis, yet almost fully prevented cartilage damage, providing another example of a major lack of correlation between inflammatory mass and destructive potential. It is suggested that novel therapy in RA patients should not only focus on reduction of outer signs of joint inflammation, but should also include attempts at reduction of cartilage destruction.
Similar content being viewed by others
References
Firestein GS, Zvaifler NJ (1990) How important are T cells in chronic rheumatoid synovitis. Arthritis Rheum 33: 768
Feldmann M, Brennan F, Maini RN (1996) Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 14: 397
Arend WP, Dayer JM (1995) Inhibition of the production and effects of IL-1 and TNFα in RA. Arthritis Rheum 38: 151
Saklatvala J (1986) Tumor necrosis factor a stimulates resorption and inhibits synthesis of proteoglycan in cartilage. Nature 322: 547
Van de Loo AAJ, Berg WB van den (1990) Effects of murine recombinant IL-1 on synovial joints in mice: measurement of patellar cartilage metabolism and joint inflammation. Ann Rheum Dis 49: 238
Henderson B, Pettipher ER (1989) Arthritogenic actions of recombinant IL-1 and TNFα in the rabbit; evidence for synergistic interactions between cytokines in vivo. Clin Exp Immunol 75: 306
Ghivizzani SC, Kang R, Georgescu HI, Lechman ER, Jaffurs D, Engle JM, Watkins SC, Tindal MH, Suchanek MK, McKenzie LR, Evans CH, Robbins PD (1997) Constitutive intea-articular expression of human IL-1β following gene transfer to rabbit synovium produces all major pathologies of human rheumatoid arthritis. J Immunol 159: 3604
Probert L, Plows D, Kontogeorgos G, Kollias G (1995) The type I IL-1 receptor acts in series with TNF-a to induce arthritis in TNF-a transgenic mice. Eur J Immunol 25: 1794
Attur MG, Patel RN, Abramson SB, Amin AR (1997) IL-17 up-regulation of nitric oxide production in human osteoarthritis cartilage. Arthritis Rheum 40: 1050
Van de Loo AAJ, Amtz OJ, Otterness IG, Berg WB van den (1992) Protection against cartilage proteoglycan synthesis inhibition by anti-interleukin 1 antibodies in experimental arthritis. J Rheumatol 19: 348
Van de Loo AAJ, Joosten LAB, Lent PLEM van, Amtz OJ, Berg WB van den (1995) Role of interleukin-1, tumor necrosis factor a and interleukin-6 in cartilage proteoglycan metabolism and destruction. Effect of in situ cytokine blocking in murine antigen- and zymosan-induced arthritis. Arthritis Rheum 38: 164
Otari K, Nita I, Macaulay W, Georgescu HI, Robbins PD, Evans CH (1996) Suppression of antigen-induced arthritis in rabbits by ex vivo gene therapy. J Immunol 156: 3558
Van Meurs JBJ, Lent PLEM van, Singer II, Bayne EK, Loo FAJ van de, Berg WB van den (1998) IL-1ra prevents expression of the metalloproteinase-generated neoepitope VDIPEN in antigen-induced arthritis. Arthritis Rheum 41: 647
Van Lent PLEM, Loo FAJ van de, Holthuysen AEM, Bersselaar LAM van den, Vermeer H, Berg WB van den (1995) Major role for IL-1 but not for TNF in early cartilage damage in immune complex arthritis in mice. J Rheumatol 22: 2250
Joosten LAB, Helsen MMA, Berg WB van den (1994) Accelerated onset of collagen-induced arthritis by remote inflammation. Clin Exp Immunol 97: 204
Joosten LAB, Lubberts E, Helsen MMA, Berg WB van den (1997) Dual role of IL-12 in early and late stages of murine collagen type II arthritis. J Immunol 159: 4094
Williams RO, Feldmann M, Maini RN (1992) Anti-TNF ameliorates joint disease in murine collageninduced arthritis. Proc Natl Acad Sci USA 89: 9784
Wooley PH, Dutcher J, Widmer MB, Gillis S (1993) Influence of a recombinant human soluble TNF receptor Fc fusion protein on type II collagen induced arthritis in mice. J Immunol 151: 6602
Van den Berg WB, Joosten LAB, Helsen MMA, Loo AAJ van de (1994) Amelioration of established murine collagen induced arthritis with anti-IL-1 treatment. Clin Exp Immunol 95: 237
Joosten LAB, Helsen MMA, Loo FAJ van de, Berg WB van den (1996) Anticytokine treatment of established type II collagen-induced arthritis in DBA/1 mice: a comparative study using anti-TNFα, antiIL-1α/β, and IL-Ira. Arthritis Rheum 39: 797
Bakker AC, Joosten LAB, Arntz OJ, Helsen MMA, Bendele A, Loo FAJ van de, Berg WB van den (1997) Prevention of murine collagen-induced arthritis in the knee and ipsilateral paw by local expression of human IL-lra protein in the knee. Arthritis Rheum 40: 893
Ku G, Faust T, Lauffer LL, Livingston DJ, Harding MW (1996) IL-1β converting enzyme inhibition blocks progression of type 11 collagen-induced arthritis in mice. Cytokine 8: 377
Pasparakis M, Alexopoulou L, Episkopou V, Kollias G (1996) Immune and inflammatory responses in TNFa-deficient mice: a critical requirement for TNFα in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J Exp Med 184: 1397
Mori L, Iselin S, De Libero G, Lesslauer W (1996) Attenuation of collagen-induced arthritis in 55-kDa TNF receptor type 1 (TNFRI)-IgG1-treated and TNFR1-deficient mice. J Immunol 157: 3178
Lens JW, Berg WB van den, Putte LBA van de, Zwarts WA (1986) Flare-up of antigen induced arthritis in mice after challenge with intravenous antigen: kinetic of antigen in the circulation and localization of antigen in the arthritic and noninflamed joint. Arthritis Rheum 29: 665
Van de Loo AAJ, Arntz OJ, Bakker AC, Lent PLEM van, MJM Jacobs, Berg WB van den (1995) Role of Interleukin-I in antigen-induced exacerbations of murine arthritis. Am J Pathol 146: 239
Van de Loo AAJ, Arntz OJ, Berg WB van den (1992) Flare-up of experimental arthritis in mice with marine recombinant IL-1. Clin Exp Immunol 87: 196
Brennan FM, Chantry D, Jackson A, Maini RN, Feldmann M (1989) Inhibitory effect of TNFa antibodies on synovial cell IL-1 production in rheumatoid arthritis. Lancet II: 244
Deleuran B (1996) Cytokines in RA; localization in arthritic joint tissue and regulation in vitro. Scand J Rheumatol 25[Suppl 104]: 1
Kuiper S, Joosten LAB, Bendele AM, Edwards CK III, Amtz OJ, Helsen MMA, Loo FAJ van de, Berg WB van den (1998) Different roles of TNFα and IL-I in murine streptococcal cell wall arthritis. Cytokine (in press)
Makarov SS, Olsen JC, Johnston WN, Anderle SK, Brown RR, Baldwin AS Jr, Haskill KS, Schwab JH (1996) Suppression of experimental arthritis by gene transfer of IL-Ira cDNA. Proc Natl Acad Sci USA 93: 402
Georgopoulos S, Plows D, Kollias G (1996) Transmembrane TNF is sufficient to induce localized tissue toxicity and chronic inflammatory arthritis in transgenic mice. J Inflamm 46: 86
Katsikis P, Chu CQ, Brennan FM, Maim RN, Feldmann M (1994) Immunoregulatory role of IL-10 in RA. J Exp Med 179: 1517
Sebbag M, Parry SL, Brennan FM, Feldmann M (1997) Cytokine stimulation of T lymphocytes regulates their capacity to induce monocyte production of TNF-α, but not IL-10: possible relevance to pathophysiology of rheumatoid arthritis. Eur J Immunol 27: 624
Miossec P, Berg WB van den (1997) Th1/Th2 cytokine balance in arthritis. Arthritis Rheum 40: 2105
Kasama T, Strieter RM, Lukacs NW, Lincoln PM, Burdick MD (1995) IL-10 expression and chemokine regulation during the evolution of marine type 11 collagen-induced arthritis. J Clin Invest 95: 2868
Joosten LAB, Lubberts E, Durez P, Helsen MMA, Jacobs MJM, Goldman M, Berg WB van den (1997) Role of IL-4 and IL-10 in murine collagen-induced arthritis: protective effect of IL-4 and IL-10 treatment on cartilage destruction. Arthritis Rheum 40: 249
Lubberts E, Joosten LAB, Helsen MMA, Berg WB van den (1998) Regulatory role of IL-10 in joint inflammation and cartilage destruction in murine streptococcal cell wall (SCW) arthritis. More therapeutic benefit with IL-4/IL-10 combination therapy than with IL-10 treatment alone. Cytokine 10: 361–369
Dechanet J, Merville P, Durand I, Banchereau J, Miossec P (1995) The ability of synoviocytes to support terminal differentiation of activated B cells may explain plasma cell accumulation in rheumatoid synovium. J Clin Invest 95: 456
Van Beuningen HM, Kraan PM van der, Amtz OJ, Berg WB van den (1994) In vivo protection against interleukin-l-induced articular cartilage damage by transforming growth factor-β1: age related differences. Ann Rheum Dis 53: 593
Glansbeek HL, Beuningen HM van, Vitters EL, Morris EA, Kraan PM van der, Berg WB van den (1997) Bone morphogenetic protein-2 stimulates articular cartilage proteoglycan synthesis in vivo but does not counteract IL-lα effects on proteoglycan synthesis and content. Arthritis Rheum 40: 1020
Glansbeek HL, Beuningen HM van, Vitters EL, Kraan PM van der, Berg WB van den (1998) Stimulation of articular cartilage repair in established arthritis by local administration of TGFβ into murine knee joints. Lab Invest 78: 133
Chu CQ, Fiels M, Abney E, Zheng RQH, Allard S, Feldmann M, Maim RN (1991) Transforming growth factor-β in rheumatoid synovial membrane and cartilage/pannus junction. Clin Exp Immunol 86: 380
Mussener A, Funa K, Klemau S, Klareskog L (1997) Dynamic expression of TGFβ and their type 1 and type II receptors in the synovial tissue of arthritic rats. Clin Exp Immunol 107: 112
Mussener A, Litton MJ, Lindroos E, Klareskog L (1997) Cytokine production in synovial tissue of mice with collagen-induced arthritis (CIA). Clin Exp Immunol 107: 485
Shah M, Foreman DM, Ferguson MWJ (1994) Neutralising antibody to TGF-β1, 2 reduces cutaneous scarring in adult rodents. J Cell Sci 107: 1137
Bogdan C, Vodovotz, Paik J, Nathan C (1994) Mechanism of suppression of nitric oxide synthase expression by IL-4 in primary mouse macrophages. J Leukoc Biol 55: 227
Jacobs MJM, Hoek AEM van den, Lent PLEM van, Loo FAJ van de, Putte LBA van de, Berg WB van den (1994) Role of interleukin-2 and interleukin-4 in exacerbations of murine antigen-induced arthritis. Immunology 83: 390
Tilg H, Trehu E, Atkins MB, Dinarello CA, Mier JW (1994) Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antaginist and soluble tumor necrosis factor receptor p55. Blood 83: 113
Van de Loo FAJ, Amtz OJ, Berg WB van den (1997) Effect of IL-1 and leukemia inhibitory factor on chondrocyte metabolism in articular cartilage from normal and IL-6-deficient mice: role of nitric-oxide and IL-6 in the suppression of proteoglycan synthesis. Cytokine 9: 453
Nakagawa S, Toritsuka Y, Wakitani S, Denno K, Tomita T, Owaki H, Kimura T, Shino K, Ochi T (1996) Bone marrow stromal cells contribute to synovial cell proliferation in rats with collagen induced arthritis. J Rheumatol 23: 2098
Alonzi T, Fattori E, Lazzaro D, Costa P, Probert L, Kollias G, De Benedetti F, Poli V, Ciliberto G (1998) IL-6 is required for the development of collagen-induced arthritis. J Exp Med 187: 461
Van de Loo FAJ, Kuiper S, Enckevort FHJ van, Amtz OJ, Berg WB van den (1997) Interleukin-6 ameliorates cartilage destruction during experimental arthritis. A study in interleukin-6-deficient mice. Am J Pathol 151: 177
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
van den Berg, W.B. Joint inflammation and cartilage destruction may occur uncoupled. Springer Semin Immunopathol 20, 149–164 (1998). https://doi.org/10.1007/BF00832004
Issue Date:
DOI: https://doi.org/10.1007/BF00832004