The role of synovial macrophages and macrophage-produced cytokines in driving aggrecanases, matrix metalloproteinases, and other destructive and inflammatory responses in osteoarthritis

Arthritis Research & Therapy - Tập 8 Số 6 - Trang 1-12 - 2006
Bondeson, Jan1, Wainwright, Shane D2, Lauder, Sarah1, Amos, Nick1, Hughes, Clare E2
1Department of Rheumatology, Cardiff University, UK
2Connective Tissue Biology Laboratories, Cardiff School of Biosciences, Cardiff University, Cardiff, UK

Tóm tắt

There is an increasing body of evidence that synovitis plays a role in the progression of osteoarthritis and that overproduction of cytokines and growth factors from the inflamed synovium can influence the production of degradative enzymes and the destruction of cartilage. In this study, we investigate the role of synovial macrophages and their main proinflammatory cytokines, interleukin (IL)-1 and tumour necrosis factor-alpha (TNF-α), in driving osteoarthritis synovitis and influencing the production of other pro- and anti-inflammatory cytokines, production of matrix metalloproteinases, and expression of aggrecanases in the osteoarthritis synovium. We established a model of cultures of synovial cells from digested osteoarthritis synovium derived from patients undergoing knee or hip arthroplasties. By means of anti-CD14-conjugated magnetic beads, specific depletion of osteoarthritis synovial macrophages from these cultures could be achieved. The CD14+-depleted cultures no longer produced significant amounts of macrophage-derived cytokines like IL-1 and TNF-α. Interestingly, there was also significant downregulation of several cytokines, such as IL-6 and IL-8 (p < 0.001) and matrix metalloproteinases 1 and 3 (p < 0.01), produced chiefly by synovial fibroblasts. To investigate the mechanisms involved, we went on to use specific downregulation of IL-1 and/or TNF-α in these osteoarthritis cultures of synovial cells. The results indicated that neutralisation of both IL-1 and TNF-α was needed to achieve a degree of cytokine (IL-6, IL-8, and monocyte chemoattractant protein-1) and matrix metalloproteinase (1, 3, 9, and 13) inhibition, as assessed by enzyme-linked immunosorbent assay and by reverse transcription-polymerase chain reaction (RT-PCR), similar to that observed in CD14+-depleted cultures. Another interesting observation was that in these osteoarthritis cultures of synovial cells, IL-1β production was independent of TNF-α, in contrast to the situation in rheumatoid arthritis. Using RT-PCR, we also demonstrated that whereas the ADAMTS4 (a disintegrin and metalloprotease with thrombospondin motifs 4) aggrecanase was driven mainly by TNF-α, ADAMTS5 was not affected by neutralisation of IL-1 and/or TNF-α. These results suggest that, in the osteoarthritis synovium, both inflammatory and destructive responses are dependent largely on macrophages and that these effects are cytokine-driven through a combination of IL-1 and TNF-α.

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citation_journal_title=Arthritis Rheum; citation_title=Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets; citation_author=JP Pelletier, J Martel-Pelletier, SB Abramson; citation_volume=44; citation_publication_date=2001; citation_pages=1237-1247; citation_doi=10.1002/1529-0131(200106)44:6<1237::AID-ART214>3.0.CO;2-F; citation_id=CR1

citation_journal_title=Ann Rheum Dis; citation_title=Synovial tissue inflammation in early and late osteoarthritis; citation_author=MJ Benito, DJ Veale, O FitzGerald, WB van den Berg, B Bresnihan; citation_volume=64; citation_publication_date=2005; citation_pages=1263-1267; citation_doi=10.1136/ard.2004.025270; citation_id=CR2

citation_journal_title=Ann Rheum Dis; citation_title=Cytokine expression in synovial membranes of patients with rheumatoid arthritis and osteoarthritis; citation_author=MN Farahat, G Yanni, R Poston, GS Panayi; citation_volume=52; citation_publication_date=1993; citation_pages=870-875; citation_doi=10.1136/ard.52.12.870; citation_id=CR3

citation_journal_title=Arthritis Rheum; citation_title=Serum cartilage oligomeric protein reflects osteoarthritis presence and severity: the Johnston County Osteoarthritis Project; citation_author=AG Clark, JM Jordan, V Vilim, JB Renner, AD Dragomir, G Luta, VB Kraus; citation_volume=42; citation_publication_date=1999; citation_pages=2356-2364; citation_doi=10.1002/1529-0131(199911)42:11<2356::AID-ANR14>3.0.CO;2-R; citation_id=CR4

citation_journal_title=Ann Rheum Dis; citation_title=Increased serum C reactive protein may reflect events that precede radiographic progression in osteoarthritis of the knee; citation_author=M Sharif, L Shepstone, CJ Elson, PA Dieppe, JR Kirwan; citation_volume=59; citation_publication_date=2000; citation_pages=71-74; citation_doi=10.1136/ard.59.1.71; citation_id=CR5

citation_journal_title=Osteoarthritis Cartilage; citation_title=C-reactive protein as a biomarker of emergent osteoarthritis; citation_author=M Sowers, M Jannausch, E Stein, D Jamadar, M Hochberg, L Lachance; citation_volume=10; citation_publication_date=2002; citation_pages=595-601; citation_doi=10.1053/joca.2002.0800; citation_id=CR6

citation_journal_title=In Vitro Cell Dev Biol Anim; citation_title=Cytokine inducible matrix metalloproteinase expression in immortalized rat chondrocytes is independent of nitric oxide stimulation; citation_author=WE Horton, I Udo, P Precht, R Balakir, K Hasty; citation_volume=34; citation_publication_date=1998; citation_pages=378-384; citation_doi=10.1007/s11626-998-0019-8; citation_id=CR7

citation_journal_title=Connect Tissue Res; citation_title=The role of cytokines as inflammatory mediators in osteoarthritis: lessons from animal models; citation_author=MB Goldring; citation_volume=40; citation_publication_date=1999; citation_pages=1-11; citation_doi=10.3109/03008209909005273; citation_id=CR8

citation_journal_title=Front Biosci; citation_title=Cytokines and their inhibitors in the pathophysiology of osteoarthritis; citation_author=J Martel-Pelletier, N Alaaeddine, JP Pelletier; citation_volume=4; citation_publication_date=1999; citation_pages=D694-703; citation_doi=10.2741/Martel; citation_id=CR9

citation_journal_title=Biorheology; citation_title=The role of cytokines in osteoarthritis pathophysiology; citation_author=JC Fernandes, J Martel-Pelletier, JP Pelletier; citation_volume=39; citation_publication_date=2002; citation_pages=237-246; citation_id=CR10

citation_journal_title=Expert Opin Biol Ther; citation_title=Anticytokine therapy for osteoarthritis; citation_author=MB Goldring; citation_volume=1; citation_publication_date=2001; citation_pages=817-829; citation_doi=10.1517/14712598.1.5.817; citation_id=CR11

citation_journal_title=Arthritis Rheum; citation_title=Lessons learnt from nine clinical trials of disease-modifying osteoarthritic drugs; citation_author=KD Brandt, SA Mazzuca; citation_volume=52; citation_publication_date=2005; citation_pages=3349-3359; citation_doi=10.1002/art.21409; citation_id=CR12

citation_journal_title=Arthritis Rheum; citation_title=Inflammation and angiogenesis in osteoarthritis; citation_author=L Haywood, DF McWilliams, CI Pearson, SE Gill, A Ganesan, D Wilson, DA Walsh; citation_volume=48; citation_publication_date=2003; citation_pages=2173-2177; citation_doi=10.1002/art.11094; citation_id=CR13

citation_journal_title=Ann Rheum Dis; citation_title=Synovial macrophage-osteoclast differentiation in inflammatory arthritis; citation_author=L Danks, A Sabokbar, R Gundle, NA Athanasou; citation_volume=61; citation_publication_date=2002; citation_pages=916-921; citation_doi=10.1136/ard.61.10.916; citation_id=CR14

citation_journal_title=Osteoarthritis Cartilage; citation_title=Synovial lining macrophages mediate osteophyte formation during experimental osteoarthritis; citation_author=AB Blom, PL van Lent, AE Holthuysen, PM van der Kraan, J Roth, N van Rooijen, WB van den Berg; citation_volume=12; citation_publication_date=2004; citation_pages=627-635; citation_doi=10.1016/j.joca.2004.03.003; citation_id=CR15

citation_journal_title=Arthritis Rheum; citation_title=Crucial role of synovial lining macrophages in the promotion of transforming growth factor beta-mediated osteophyte formation; citation_author=PL van Lent, AB Blom, P van der Kraan, AE Holthuysen, E Vitters, N van Rooijen, RL Smeets, KC Nabbe, WB van den Berg; citation_volume=50; citation_publication_date=2004; citation_pages=103-111; citation_doi=10.1002/art.11422; citation_id=CR16

citation_journal_title=Front Biosci; citation_title=Degradative enzymes in osteoarthritis; citation_author=RL Smith; citation_volume=4; citation_publication_date=1999; citation_pages=D704-712; citation_id=CR17

citation_journal_title=Ann Rheum Dis; citation_title=Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids from patients with rheumatoid arthritis or osteoarthritis; citation_author=Y Yoshihara, H Nakamura, K Obata, H Yamada, T Hayakawa, K Fujikawa, Y Okada; citation_volume=59; citation_publication_date=2000; citation_pages=455-461; citation_doi=10.1136/ard.59.6.455; citation_id=CR18

citation_journal_title=Arthritis Rheum; citation_title=Using inhibitors of metalloproteinases to treat arthritis. Easier said than done?; citation_author=MP Vincenti, IM Clark, CE Brinckerhoff; citation_volume=37; citation_publication_date=1994; citation_pages=1115-1126; citation_doi=10.1002/art.1780370802; citation_id=CR19

citation_journal_title=Ann N Y Acad Sci; citation_title=Clinical trials of a stromelysin inhibitor. Osteoarthritis, matrix metalloproteinase inhibition, cartilage loss, surrogate markers, and clinical implications; citation_author=RL Leff; citation_volume=878; citation_publication_date=1999; citation_pages=201-207; citation_doi=10.1111/j.1749-6632.1999.tb07685.x; citation_id=CR20

citation_journal_title=Ann N Y Acad Sci; citation_title=Design and synthetic considerations of matrix metalloproteinase inhibitors; citation_author=JS Skotnicki, A Zask, FC Nelson, JD Albright, JI Levin; citation_volume=878; citation_publication_date=1999; citation_pages=61-72; citation_doi=10.1111/j.1749-6632.1999.tb07674.x; citation_id=CR21

citation_journal_title=Biochem J; citation_title=Aggrecanase versus matrix metalloproteinases in the catabolism of the interglobular domain of aggrecan in vitro; citation_author=CB Little, CR Flannery, CE Hughes, JS Mort, PJ Roughley, C Dent, B Caterson; citation_volume=344; citation_publication_date=1999; citation_pages=61-68; citation_id=CR22

citation_journal_title=Matrix Biol; citation_title=Mechanisms involved in cartilage proteoglycan catabolism; citation_author=B Caterson, CR Flannery, CE Hughes, CB Little; citation_volume=19; citation_publication_date=2000; citation_pages=333-344; citation_doi=10.1016/S0945-053X(00)00078-0; citation_id=CR23

citation_journal_title=Science; citation_title=Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins; citation_author=MD Tortorella, TC Burn, MA Pratta, I Abbaszade, JM Hollis, R Liu, SA Rosenfeld, RA Copeland, CP Decicco, R Wynn; citation_volume=284; citation_publication_date=1999; citation_pages=1664-1666; citation_doi=10.1126/science.284.5420.1664; citation_id=CR24

citation_journal_title=J Biol Chem; citation_title=Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family; citation_author=I Abbaszade, RQ Liu, F Yang, SA Rosenfeld, OH Ross, JR Link, DM Ellis, MD Tortorella, MA Pratta, JM Hollis; citation_volume=274; citation_publication_date=1999; citation_pages=23443-23450; citation_doi=10.1074/jbc.274.33.23443; citation_id=CR25

citation_journal_title=Osteoarthritis Cartilage; citation_title=The role of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) in a model of cartilage degradation; citation_author=MD Tortorella, AM Malfait, C Deccico, E Arner; citation_volume=9; citation_publication_date=2001; citation_pages=539-552; citation_doi=10.1053/joca.2001.0427; citation_id=CR26

citation_journal_title=Arthritis Rheum; citation_title=Pathologic indicators of degradation and inflammation in human osteoarthritic cartilage are abrogated by exposure to n-3 fatty acids; citation_author=CL Curtis, SG Rees, CB Little, CR Flannery, CE Hughes, C Wilson, CM Dent, IG Otterness, JL Harwood, B Caterson; citation_volume=46; citation_publication_date=2002; citation_pages=1544-1553; citation_doi=10.1002/art.10305; citation_id=CR27

citation_journal_title=Rheumatology (Oxford); citation_title=Adenoviral gene transfer into osteoarthritis synovial cells using the endogenous inhibitor IκBα reveals that most, but not all, inhibitory and destructive mediators, are NFκB dependent; citation_author=N Amos, S Lauder, A Evans, M Feldmann, J Bondeson; citation_volume=45; citation_publication_date=2006; citation_pages=1201-1209; citation_doi=10.1093/rheumatology/kel078; citation_id=CR28

Brennan FM, Chantry D, Jackson AM, Maini RN, Feldmann M: Cytokine production in culture by cells isolated from the synovial membrane. J Autoimmun. 1989, 177-186. 10.1016/0896-8411(89)90129-7. 2 Suppl

citation_journal_title=Biotechniques; citation_title=Rapid isolation of total RNA from small samples of hypocellular, dense connective tissue; citation_author=C Reno, L Marchuk, P Sciore, CB Frank, DA Hart; citation_volume=22; citation_publication_date=1997; citation_pages=1082-1088; citation_id=CR30

citation_journal_title=Biochem J; citation_title=Catabolism of aggrecan, decorin and biglycan in tendon; citation_author=SG Rees, CR Flannery, CB Little, CE Hughes, B Caterson, CM Dent; citation_volume=350; citation_publication_date=2000; citation_pages=181-188; citation_doi=10.1042/bj3500181; citation_id=CR31

citation_journal_title=Lancet; citation_title=Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis; citation_author=FM Brennan, D Chantry, A CJackson, R Maini, M Feldmann; citation_volume=2; citation_publication_date=1989; citation_pages=244-247; citation_doi=10.1016/S0140-6736(89)90430-3; citation_id=CR32

citation_journal_title=Matrix Biol; citation_title=An alternatively spliced transcript of ADAMTS4 is present in human synovium from OA patients; citation_author=SD Wainwright, J Bondeson, CE Hughes; citation_volume=25; citation_publication_date=2006; citation_pages=317-320; citation_doi=10.1016/j.matbio.2006.03.006; citation_id=CR33

citation_journal_title=Scand J Rheumatol; citation_title=Usefulness of high resolution US in the evaluation of effusion in osteoarthritic first carpometacarpal joint; citation_author=A Iagnocco, G Coari; citation_volume=29; citation_publication_date=2000; citation_pages=170-173; citation_doi=10.1080/030097400750002049; citation_id=CR34

citation_journal_title=J Rheumatol; citation_title=High resolution ultrasonography in detection of bone erosions in patients with hand osteoarthritis; citation_author=A Iagnocco, E Filippucci, A Ossandon, A Ciapetti, F Salaffi, S Basili, W Grassi, G Valesini; citation_volume=32; citation_publication_date=2005; citation_pages=2381-2383; citation_id=CR35

citation_journal_title=Arthritis Rheum; citation_title=Macroscopic and microscopic features of synovial membrane inflammation in the osteoarthritic knee: correlating magnetic resonance imagings with disease severity; citation_author=D Loeuille, I Chary-Valckenaere, J Champigneulle, AC Rat, F Toussaint, A Pinzano-Watrin, JC Goebel, D Mainard, A Blum, J Pourel; citation_volume=52; citation_publication_date=2005; citation_pages=3492-3501; citation_doi=10.1002/art.21373; citation_id=CR36

citation_journal_title=Arthritis Rheum; citation_title=Effects of intraarticular glucocorticoids on macrophage infiltration and mediators of joint damage in osteoarthritis synovial membranes: findings in a double-blind, placebo-controlled study; citation_author=L Young, A Katrib, C Cuello, U Vollmer-Conna, JV Bertouch, PJ Roberts-Thomson, MJ Ahern, MD Smith, PP Youssef; citation_volume=44; citation_publication_date=2001; citation_pages=343-350; citation_doi=10.1002/1529-0131(200102)44:2<343::AID-ANR52>3.0.CO;2-Q; citation_id=CR37

citation_journal_title=Proc Natl Acad Sci USA; citation_title=Defining therapeutic targets by using adenovirus: blocking NF-κB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators; citation_author=J Bondeson, B Foxwell, F Brennan, M Feldmann; citation_volume=96; citation_publication_date=1999; citation_pages=5668-5673; citation_doi=10.1073/pnas.96.10.5668; citation_id=CR38

citation_journal_title=Nat Rev Immunol; citation_title=Development of anti-TNF therapy for rheumatoid arthritis; citation_author=M Feldmann; citation_volume=2; citation_publication_date=2002; citation_pages=364-371; citation_doi=10.1038/nri802; citation_id=CR39

citation_journal_title=Proc Natl Acad Sci USA; citation_title=Efficient adenoviral infection with IκBα reveals that macrophage TNFα production in rheumatoid arthritis is NF-κB dependent; citation_author=B Foxwell, K Browne, J Bondeson, CJ Clarke, R de Martin, F Brennan, M Feldmann; citation_volume=95; citation_publication_date=1998; citation_pages=8211-8215; citation_doi=10.1073/pnas.95.14.8211; citation_id=CR40

citation_journal_title=J Immunol; citation_title=Selective regulation of cytokine induction by adenoviral gene transfer of IκBα into human macrophages: lipopolysaccharide-induced, but not zymosan-induced, proinflammatory cytokines are inhibited, but IL-10 is NFκB independent; citation_author=J Bondeson, KA Browne, FM Brennan, BM Foxwell, M Feldmann; citation_volume=162; citation_publication_date=1999; citation_pages=2939-2945; citation_id=CR41

citation_journal_title=J Biol Chem; citation_title=CD45-induced tumor necrosis factor alpha production in monocytes is phosphatidylinositol 3-kinase-dependent and nuclear factor kappaB-independent; citation_author=AL Hayes, C Smith, BM Foxwell, FM Brennan; citation_volume=274; citation_publication_date=1999; citation_pages=33455-33461; citation_doi=10.1074/jbc.274.47.33455; citation_id=CR42

citation_journal_title=Arthritis Rheum; citation_title=Evidence that rheumatoid arthritis synovial T cells are similar to cytokine-activated T cells: involvement of phosphatidylinositol 3-kinase and nuclear factor kappaB pathways in tumour necrosis factor alpha production in rheumatoid arthritis; citation_author=FM Brennan, AL Hayes, CJ Ciesielski, P Green, BM Foxwell, M Feldmann; citation_volume=46; citation_publication_date=2002; citation_pages=31-41; citation_doi=10.1002/1529-0131(200201)46:1<31::AID-ART10029>3.0.CO;2-5; citation_id=CR43

citation_journal_title=Arthritis Rheum; citation_title=Heterogenous requirement of IkappaB kinase 2 for inflammatory cytokine and matrix metalloproteinase production in rheumatoid arthritis: implications for therapy; citation_author=E Andreakos, C Smith, S Kiriakidis, C Monaco, R de Martin, FM Brennan, E Paleolog, M Feldmann, BM Foxwell; citation_volume=48; citation_publication_date=2003; citation_pages=1901-1912; citation_doi=10.1002/art.11044; citation_id=CR44

citation_journal_title=J Rheumatol; citation_title=Safety study of intraarticular injection of interleukin 1 receptor antagonist in patients with painful knee osteoarthritis: a multicenter study; citation_author=X Chevalier, B Girardeau, T Conzorier, J Marliere, P Kiefer, P Goupille; citation_volume=32; citation_publication_date=2005; citation_pages=1317-1323; citation_id=CR45

citation_journal_title=Ann Rheum Dis; citation_title=Successful treatment of inflammatory knee osteoarthritis with tumour necrosis factor blockade; citation_author=M Grunke, H Schulze-Koops; citation_volume=65; citation_publication_date=2006; citation_pages=555-556; citation_doi=10.1136/ard.2006.053272; citation_id=CR46

citation_journal_title=Arthritis Rheum; citation_title=Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro; citation_author=B Bau, PM Gebhard, J Haag, T Knorr, E Bartnik, T Aigner; citation_volume=46; citation_publication_date=2002; citation_pages=2648-2657; citation_doi=10.1002/art.10531; citation_id=CR47

citation_journal_title=Arthritis Rheum; citation_title=Induction of aggrecanase-1 (ADAM-TS4) by interleukin-1 occurs through activation of constitutively produced protein; citation_author=MA Pratta, PA Scherle, G Yang, RQ Liu, RC Newton; citation_volume=48; citation_publication_date=2003; citation_pages=119-133; citation_doi=10.1002/art.10726; citation_id=CR48

Bondeson J, Lauder S, Wainwright S, Amos N, Evans A, Hughes C, Feldmann M, Caterson B: Adenoviral gene transfer of the endogenous inhibitor IκBα into human osteoarthritis synovial fibroblasts demonstrates that several matrix metalloproteinases and aggrecanases are nuclear factor-κB dependent. J Rheumatol.

citation_journal_title=Arthritis Rheum; citation_title=Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice; citation_author=SS Glasson, R Askew, B Sheppard, BA Carito, T Blanchet, HL Ma, CR Flannery, K Kanki, E Wang, D Peluso; citation_volume=50; citation_publication_date=2004; citation_pages=2547-2558; citation_doi=10.1002/art.20558; citation_id=CR50

citation_journal_title=Nature; citation_title=Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis; citation_author=SS Glasson, R Askew, B Sheppard, B Carito, T Blanchet, HL Ma, CR Flannery, D Peluso, K Kanki, Z Yang; citation_volume=434; citation_publication_date=2005; citation_pages=644-648; citation_doi=10.1038/nature03369; citation_id=CR51

citation_journal_title=Nature; citation_title=ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro; citation_author=H Stanton, FM Rogerson, CJ East, SB Golub, KE Lawlor, CT Meeker, CB Little, K Last, PJ Farmer, IK Campbell; citation_volume=434; citation_publication_date=2005; citation_pages=648-652; citation_doi=10.1038/nature03417; citation_id=CR52

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