[en] INTRODUCTION: This work aimed at comparing the production of inflammatory and pro- and anti-angiogenic factors by normal/reactive (N/R) or inflammatory (I) areas of the osteoarthritic synovial membrane. The effects of interleukin (IL)-1β and chondroitin sulfate (CS) on the expression of pro- and anti-angiogenic factors by synovial fibroblasts cells (SFC) were also studied.
METHODS:
Biopsies from N/R or from I areas of osteoarthritic synovial membrane were collected at the time of surgery. The inflammatory status of the synovial membrane was characterized by the surgeon according to macroscopic criteria, including the synovial vascularization, the villi formation and the hypertrophic aspect of the tissue. We assessed the expression of CD45, von Willebrand factor and vascular endothelial growth factor (VEGF) antigen by immunohistochemistry in both N/R and I biopsies. The production of IL-6, -8, VEGF and thrombospondin (TSP)-1 by N/R or I synovial cells was quantified by ELISA. SFC were cultured in the absence or in the presence of IL-1β (1 ng/ml) and with or without CS (10, 50, 200 μg/ml). Gene expression of pro-angiogenic factors (VEGF, basic fibroblast growth factor (bFGF), nerve growth factor (NGF), matrix metalloproteinase (MMP)-2 and angiopoietin (ang)-1) and anti-angiogenic factors (vascular endothelial growth inhibitor (VEGI), TSP-1 and -2) were determined by real time RT-PCR. Production of VEGI and TSP-1 was also estimated by ELISA.
RESULTS:
Immunohistochemistry showed the increase of lymphocyte infiltration, vascular density and VEGF expression in I compared to N/R synovial biopsies. Synovial cells from I areas produced more IL-6, IL-8 and VEGF but less TSP-1 than cells isolated from N/R synovial biopsies. The expression of pro-angiogenic factors by SFC was stimulated by IL-1β. A time dependent regulation of the expression of anti-angiogenic factor genes was observed. IL-1β stimulated the expression of anti-angiogenic factor genes but inhibited it after 24 h. CS reversed the inhibitory effect of IL-1β on anti-angiogenic factors, VEGI and TSP-1.
CONCLUSIONS:
We demonstrated that synovial biopsies from I areas expressed a pro-angiogenic phenotype. IL-1β induced an imbalance between pro- and anti-angiogenic factors in SFC and CS tended to normalize this IL-1β-induced imbalance, providing a new possible mechanism of action of this drug.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Lambert, Cécile ; Université de Liège - ULiège > Département des sciences de la motricité > Unité de recherche sur l'os et le cartillage (U.R.O.C.)
Mathy-Hartert, Marianne
Dubuc, JE
Montell, E
Vergés, J
Munaut, Carine ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Henrotin, Yves ; Université de Liège - ULiège > Département des sciences de la motricité > Unité de recherche sur l'os et le cartillage (U.R.O.C.)
Language :
English
Title :
Characterization of synovial angiogenesis in osteoarthritis patients and its modulation by chondroitin sulfate
Haywood L, McWilliams DF, Pearson CI, Gill SE, Ganesan A, Wilson D, Walsh DA. Inflammation and angiogenesis in osteoarthritis. Arthritis Rheum 2003, 48:2173-2177. 10.1002/art.11094, 12905470.
Walsh DA, Bonnet CS, Turner EL, Wilson D, Situ M, McWilliams DF. Angiogenesis in the synovium and at the osteochondral junction in osteoarthritis. Osteoarthritis Cartilage 2007, 15:743-751. 10.1016/j.joca.2007.01.020, 17376709.
Papetti M, Herman IM. Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol 2002, 282:C947-970.
Nico B, Mangieri D, Benagiano V, Crivellato E, Ribatti D. Nerve growth factor as an angiogenic factor. Microvasc Res 2008, 75:135-141. 10.1016/j.mvr.2007.07.004, 17764704.
Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 1996, 87:1171-1180. 10.1016/S0092-8674(00)81813-9, 8980224.
Pepper MS. Role of the matrix metalloproteinase and plasminogen activator-plasmin systems in angiogenesis. Arterioscler Thromb Vasc Biol 2001, 21:1104-1117. 10.1161/hq0701.093685, 11451738.
Bornstein P. Thrombospondins function as regulators of angiogenesis. J Cell Commun Signal 2009, 3:189-200. 10.1007/s12079-009-0060-8, 2778581,2778581, 19798599.
Yu J, Tian S, Metheny-Barlow L, Chew LJ, Hayes AJ, Pan H, Yu GL, Li LY. Modulation of endothelial cell growth arrest and apoptosis by vascular endothelial growth inhibitor. Circ Res 2001, 89:1161-1167. 10.1161/hh2401.101909, 11739281.
Koch AE, Harlow LA, Haines GK, Amento EP, Unemori EN, Wong WL, Pope RM, Ferrara N. Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J Immunol 1994, 152:4149-4156.
Nakashima M, Eguchi K, Aoyagi T, Yamashita I, Ida H, Sakai M, Shimada H, Kawabe Y, Nagataki S, Koji T. Expression of basic fibroblast growth factor in synovial tissues from patients with rheumatoid arthritis: detection by immunohistological staining and in situ hybridisation. Ann Rheum Dis 1994, 53:45-50. 10.1136/ard.53.1.45, 1005242, 8311555.
Barthel C, Yeremenko N, Jacobs R, Schmidt RE, Bernateck M, Zeidler H, Tak PP, Baeten D, Rihl M. Nerve growth factor and receptor expression in rheumatoid arthritis and spondyloarthritis. Arthritis Res Ther 2009, 11:R82. 10.1186/ar2716, 2714133, 19490633.
Shahrara S, Volin MV, Connors MA, Haines GK, Koch AE. Differential expression of the angiogenic Tie receptor family in arthritic and normal synovial tissue. Arthritis Res 2002, 4:201-208. 10.1186/ar407, 111023, 12010571.
Goldbach-Mansky R, Lee JM, Hoxworth JM, Smith D, Duray P, Schumacher RH, Yarboro CH, Klippel J, Kleiner D, El-Gabalawy HS. Active synovial matrix metalloproteinase-2 is associated with radiographic erosions in patients with early synovitis. Arthritis Res 2000, 2:145-153. 10.1186/ar79, 17808, 11062605.
Gotis-Graham I, Hogg PJ, McNeil HP. Significant correlation between thrombospondin 1 and serine proteinase expression in rheumatoid synovium. Arthritis Rheum 1997, 40:1780-1787. 10.1002/art.1780401009, 9336411.
Park YW, Kang YM, Butterfield J, Detmar M, Goronzy JJ, Weyand CM. Thrombospondin 2 functions as an endogenous regulator of angiogenesis and inflammation in rheumatoid arthritis. Am J Pathol 2004, 165:2087-2098. 10.1016/S0002-9440(10)63259-2, 1618704, 15579451.
Cassatella MA, Pereira-da-Silva G, Tinazzi I, Facchetti F, Scapini P, Calzetti F, Tamassia N, Wei P, Nardelli B, Roschke V, Vecchi A, Mantovani A, Bambara LM, Edwards SW, Carletto A. Soluble TNF-like cytokine (TL1A) production by immune complexes stimulated monocytes in rheumatoid arthritis. J Immunol 2007, 178:7325-7333. Erratum in J Immunol 2007, 179:1390. da Silva, Gabriela Pereira (corrected to Pereira da-Silva, Gabriela).
Leeb BF, Schweitzer H, Montag K, Smolen JS. A metaanalysis of chondroitin sulfate in the treatment of osteoarthritis. J Rheumatol 2000, 27:205-211.
McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA 2000, 283:1469-1475. 10.1001/jama.283.11.1469, 10732937.
Richy F, Bruyere O, Ethgen O, Cucherat M, Henrotin Y, Reginster JY. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis. Arch Intern Med 2003, 163:1514-1522. 10.1001/archinte.163.13.1514, 12860572.
Hochberg MC. Structure-modifying effects of chondroitin sulfate in knee osteoarthritis: an updated meta-analysis of randomized placebo-controlled trials of 2-year duration. Osteoarthritis Cartilage 2010, 18(Suppl 1):S28-31.
Hochberg MC, Zhan M, Langenberg P. The rate of decline of joint space width in patients with osteoarthritis of the knee: a systematic review and meta-analysis of randomized placebo-controlled trials of chondroitin sulfate. Curr Med Res Opin 2008, 24:3029-3035. 10.1185/03007990802434932, 18826751.
Monfort J, Pelletier JP, Garcia-Giralt N, Martel-Pelletier J. Biochemical basis of the effect of chondroitin sulphate on osteoarthritis articular tissues. Ann Rheum Dis 2008, 67:735-740. 10.1136/ard.2006.068882, 17644553.
Martel-Pelletier J, Kwan Tat S, Pelletier JP. Effects of chondroitin sulfate in the pathophysiology of the osteoarthritic joint: a narrative review. Osteoarthritis Cartilage 2010, 18(Suppl 1):S7-11.
Lauder RM. Chondroitin sulphate: a complex molecule with potential impacts on a wide range of biological systems. Complement Ther Med 2009, 17:56-62. 10.1016/j.ctim.2008.08.004, 19114230.
Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, Bradley JD, Bingham CO, Weisman MH, Jackson CG, Lane NE, Cush JJ, Moreland LW, Schumacher HR, Oddis CV, Wolfe F, Molitor JA, Yocum DE, Schnitzer TJ, Furst DE, Sawitzke AD, Shi H, Brandt KD, Moskowitz RW, Williams HJ. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006, 354:795-808. 10.1056/NEJMoa052771, 16495392.
Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol 2010, 6:625-635. 10.1038/nrrheum.2010.159, 20924410.
Labarca C, Paigen K. A simple, rapid, and sensitive DNA assay procedure. Anal Biochem 1980, 102:344-352. 10.1016/0003-2697(80)90165-7, 6158890.
Bonnet CS, Walsh DA. Osteoarthritis, angiogenesis and inflammation. Rheumatology (Oxford) 2005, 44:7-16.
Pearle AD, Scanzello CR, George S, Mandl LA, DiCarlo EF, Peterson M, Sculco TP, Crow MK. Elevated high-sensitivity C-reactive protein levels are associated with local inflammatory findings in patients with osteoarthritis. Osteoarthritis Cartilage 2007, 15:516-523. 10.1016/j.joca.2006.10.010, 17157039.
Hsieh JL, Shen PC, Shiau AL, Jou IM, Lee CH, Wang CR, Teo ML, Wu CL. Intraarticular gene transfer of thrombospondin-1 suppresses the disease progression of experimental osteoarthritis. J Orthop Res 2010, 28:1300-1306. 10.1002/jor.21134, 20309955.
Jackson JR, Minton JA, Ho ML, Wei N, Winkler JD. Expression of vascular endothelial growth factor in synovial fibroblasts is induced by hypoxia and interleukin 1beta. J Rheumatol 1997, 24:1253-1259.
Manni L, Lundeberg T, Fiorito S, Bonini S, Vigneti E, Aloe L. Nerve growth factor release by human synovial fibroblasts prior to and following exposure to tumor necrosis factor-alpha, interleukin-1 beta and cholecystokinin-8: the possible role of NGF in the inflammatory response. Clin Exp Rheumatol 2003, 21:617-624.
Gravallese EM, Pettit AR, Lee R, Madore R, Manning C, Tsay A, Gaspar J, Goldring MB, Goldring SR, Oettgen P. Angiopoietin-1 is expressed in the synovium of patients with rheumatoid arthritis and is induced by tumour necrosis factor alpha. Ann Rheum Dis 2003, 62:100-107. 10.1136/ard.62.2.100, 1754433, 12525377.
Lyons-Giordano B, Kefalides NA, Brinker JM, Pratta MA, Arner EC. The effects of interleukin-1 on the expression of thrombospondin and fibronectin by rabbit articular chondrocytes. Exp Cell Res 1991, 195:462-467. 10.1016/0014-4827(91)90397-D, 2070828.
Morandi V, Cherradi SE, Lambert S, Fauvel-Lafeve F, Legrand YJ, Legrand C. Proinflammatory cytokines (interleukin-1 beta and tumor necrosis factor-alpha) down regulate synthesis and secretion of thrombospondin by human endothelial cells. J Cell Physiol 1994, 160:367-377. 10.1002/jcp.1041600218, 8040193.
Migone TS, Zhang J, Luo X, Zhuang L, Chen C, Hu B, Hong JS, Perry JW, Chen SF, Zhou JX, Cho YH, Ullrich S, Kanakaraj P, Carrell J, Boyd E, Olsen HS, Hu G, Pukac L, Liu D, Ni J, Kim S, Gentz R, Feng P, Moore PA, Ruben SM, Wei P. TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator. Immunity 2002, 16:479-492. 10.1016/S1074-7613(02)00283-2, 11911831.
Iovu M, Dumais G, du Souich P. Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis Cartilage 2008, 16(Suppl 3):S14-18.
Pollard JW. Macrophages define the invasive microenvironment in breast cancer. J Leukoc Biol 2008, 84:623-630. 10.1189/jlb.1107762, 2516896, 18467655.
Liu Y, Yang H, Otaka K, Takatsuki H, Sakanishi A. Effects of vascular endothelial growth factor (VEGF) and chondroitin sulfate A on human monocytic THP-1 cell migration. Colloids Surf B Biointerfaces 2005, 43:216-220. 10.1016/j.colsurfb.2005.04.011, 15978788.
