Logo of annrheumdAnnals of the Rheumatic DiseasesVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
Ann Rheum Dis. 2003 Feb; 62(2): 100–107.
PMCID: PMC1754433

Angiopoietin-1 is expressed in the synovium of patients with rheumatoid arthritis and is induced by tumour necrosis factor α


Objectives: To examine the potential role of the angiogenic growth factor angiopoietin-1 (Ang-1) in inflammatory arthritis.

Methods: Eighteen synovial tissue samples were obtained from 17 patients with a clinical diagnosis of rheumatoid arthritis (RA) and compared with six synovial tissue samples from six patients with osteoarthritis (OA). Ang-1 expression in synovial tissues was determined by immunohistochemistry and in situ hybridisation. Ang-1 mRNA and protein expression were also examined by northern blot analysis and enzyme linked immunosorbent assay (ELISA) in cultured synovial fibroblasts and human umbilical vein endothelial cells (HUVECs) before and after treatment with tumour necrosis factor (TNF)α.

Results: Ang-1 protein expression was detected by immunohistochemistry in 16/18 RA synovial tissue samples. Ang-1 protein was frequently observed in the synovial lining layer and in cells within the sublining synovial tissue, in both perivascular areas and in areas remote from vessels. In contrast, Ang-1 was only weakly detected in these sites in OA samples. Ang-1 mRNA and protein were also expressed in cultured synovial fibroblasts derived from patients with RA. In addition, induction of Ang-1 mRNA and protein was observed by northern blot analysis and ELISA after stimulation of RA synovial fibroblasts, but not HUVECs, with the proinflammatory cytokine TNFα.

Conclusions: Ang-1 mRNA and protein are expressed in the synovium of patients with RA, and are up regulated in synovial fibroblasts by TNFα. Ang-1 may therefore be an important regulator of angiogenesis in inflammatory arthritis.

Full Text

The Full Text of this article is available as a PDF (271K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Jackson JR, Seed MP, Kircher CH, Willoughby DA, Winkler JD. The codependence of angiogenesis and chronic inflammation. FASEB J. 1997 May;11(6):457–465. [PubMed]
  • Koch AE. Review: angiogenesis: implications for rheumatoid arthritis. Arthritis Rheum. 1998 Jun;41(6):951–962. [PubMed]
  • Walsh DA. Angiogenesis and arthritis. Rheumatology (Oxford) 1999 Feb;38(2):103–112. [PubMed]
  • 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 Dec 27;87(7):1171–1180. [PubMed]
  • Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997 Jul 4;277(5322):55–60. [PubMed]
  • FitzGerald O, Soden M, Yanni G, Robinson R, Bresnihan B. Morphometric analysis of blood vessels in synovial membranes obtained from clinically affected and unaffected knee joints of patients with rheumatoid arthritis. Ann Rheum Dis. 1991 Nov;50(11):792–796. [PMC free article] [PubMed]
  • Pando JA, Duray P, Yarboro C, Gourley MF, Klippel JH, Schumacher HR. Synovitis occurs in some clinically normal and asymptomatic joints in patients with early arthritis. J Rheumatol. 2000 Aug;27(8):1848–1854. [PubMed]
  • Stevens CR, Blake DR, Merry P, Revell PA, Levick JR. A comparative study by morphometry of the microvasculature in normal and rheumatoid synovium. Arthritis Rheum. 1991 Dec;34(12):1508–1513. [PubMed]
  • Cleland LG. Animal models of rheumatoid arthritis. Br J Rheumatol. 1996 Nov;35(11):1041–1042. [PubMed]
  • Peacock DJ, Banquerigo ML, Brahn E. Angiogenesis inhibition suppresses collagen arthritis. J Exp Med. 1992 Apr 1;175(4):1135–1138. [PMC free article] [PubMed]
  • Walsh DA, Wade M, Mapp PI, Blake DR. Focally regulated endothelial proliferation and cell death in human synovium. Am J Pathol. 1998 Mar;152(3):691–702. [PMC free article] [PubMed]
  • Qu Z, Huang XN, Ahmadi P, Andresevic J, Planck SR, Hart CE, Rosenbaum JT. Expression of basic fibroblast growth factor in synovial tissue from patients with rheumatoid arthritis and degenerative joint disease. Lab Invest. 1995 Sep;73(3):339–346. [PubMed]
  • Fava RA, Olsen NJ, Spencer-Green G, Yeo KT, Yeo TK, Berse B, Jackman RW, Senger DR, Dvorak HF, Brown LF. Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J Exp Med. 1994 Jul 1;180(1):341–346. [PMC free article] [PubMed]
  • Chu CQ, Field M, Abney E, Zheng RQ, Allard S, Feldmann M, Maini RN. Transforming growth factor-beta 1 in rheumatoid synovial membrane and cartilage/pannus junction. Clin Exp Immunol. 1991 Dec;86(3):380–386. [PMC free article] [PubMed]
  • Goddard DH, Grossman SL, Williams WV, Weiner DB, Gross JL, Eidsvoog K, Dasch JR. Regulation of synovial cell growth. Coexpression of transforming growth factor beta and basic fibroblast growth factor by cultured synovial cells. Arthritis Rheum. 1992 Nov;35(11):1296–1303. [PubMed]
  • Koch AE, Halloran MM, Hosaka S, Shah MR, Haskell CJ, Baker SK, Panos RJ, Haines GK, Bennett GL, Pope RM, et al. Hepatocyte growth factor. A cytokine mediating endothelial migration in inflammatory arthritis. Arthritis Rheum. 1996 Sep;39(9):1566–1575. [PubMed]
  • Nagashima M, Hasegawa J, Kato K, Yamazaki J, Nishigai K, Ishiwata T, Asano G, Yoshino S. Hepatocyte growth factor (HGF), HGF activator, and c-Met in synovial tissues in rheumatoid arthritis and osteoarthritis. J Rheumatol. 2001 Aug;28(8):1772–1778. [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]
  • Gravallese EM, Harada Y, Wang JT, Gorn AH, Thornhill TS, Goldring SR. Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis. Am J Pathol. 1998 Apr;152(4):943–951. [PMC free article] [PubMed]
  • Scott Boyd B, Zaratin Paola F, Colombo Antonio, Hansbury Michael J, Winkler James D, Jackson Jeffrey R. Constitutive expression of angiopoietin-1 and -2 and modulation of their expression by inflammatory cytokines in rheumatoid arthritis synovial fibroblasts. J Rheumatol. 2002 Feb;29(2):230–239. [PubMed]
  • Shahrara Shiva, Volin Michael V, Connors Matthew A, Haines G Kenneth, Koch Alisa E. Differential expression of the angiogenic Tie receptor family in arthritic and normal synovial tissue. Arthritis Res. 2002;4(3):201–208. [PMC free article] [PubMed]
  • Zimmermann T, Kunisch E, Pfeiffer R, Hirth A, Stahl HD, Sack U, Laube A, Liesaus E, Roth A, Palombo-Kinne E, et al. Isolation and characterization of rheumatoid arthritis synovial fibroblasts from primary culture--primary culture cells markedly differ from fourth-passage cells. Arthritis Res. 2001;3(1):72–76. [PMC free article] [PubMed]
  • Unemori EN, Hibbs MS, Amento EP. Constitutive expression of a 92-kD gelatinase (type V collagenase) by rheumatoid synovial fibroblasts and its induction in normal human fibroblasts by inflammatory cytokines. J Clin Invest. 1991 Nov;88(5):1656–1662. [PMC free article] [PubMed]
  • Tsai C, Diaz LA, Jr, Singer NG, Li LL, Kirsch AH, Mitra R, Nickoloff BJ, Crofford LJ, Fox DA. Responsiveness of human T lymphocytes to bacterial superantigens presented by cultured rheumatoid arthritis synoviocytes. Arthritis Rheum. 1996 Jan;39(1):125–136. [PubMed]
  • Giatromanolaki A, Sivridis E, Brekken R, Thorpe PE, Anastasiadis P, Gatter KC, Harris AL, Koukourakis MI. The angiogenic "vascular endothelial growth factor/flk-1(KDR) receptor" pathway in patients with endometrial carcinoma: prognostic and therapeutic implications. Cancer. 2001 Nov 15;92(10):2569–2577. [PubMed]
  • Pufe T, Petersen W, Tillmann B, Mentlein R. The splice variants VEGF121 and VEGF189 of the angiogenic peptide vascular endothelial growth factor are expressed in osteoarthritic cartilage. Arthritis Rheum. 2001 May;44(5):1082–1088. [PubMed]
  • Witzenbichler B, Maisonpierre PC, Jones P, Yancopoulos GD, Isner JM. Chemotactic properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor tyrosine kinase Tie2. J Biol Chem. 1998 Jul 17;273(29):18514–18521. [PubMed]
  • Fujikawa K, de Aos Scherpenseel I, Jain SK, Presman E, Christensen RA, Varticovski L. Role of PI 3-kinase in angiopoietin-1-mediated migration and attachment-dependent survival of endothelial cells. Exp Cell Res. 1999 Dec 15;253(2):663–672. [PubMed]
  • Huang XL, Takakura N, Suda T. In vitro effects of angiopoietins and VEGF on hematopoietic and endothelial cells. Biochem Biophys Res Commun. 1999 Oct 14;264(1):133–138. [PubMed]
  • Suri C, McClain J, Thurston G, McDonald DM, Zhou H, Oldmixon EH, Sato TN, Yancopoulos GD. Increased vascularization in mice overexpressing angiopoietin-1. Science. 1998 Oct 16;282(5388):468–471. [PubMed]
  • Storgard CM, Stupack DG, Jonczyk A, Goodman SL, Fox RI, Cheresh DA. Decreased angiogenesis and arthritic disease in rabbits treated with an alphavbeta3 antagonist. J Clin Invest. 1999 Jan;103(1):47–54. [PMC free article] [PubMed]
  • Miotla J, Maciewicz R, Kendrew J, Feldmann M, Paleolog E. Treatment with soluble VEGF receptor reduces disease severity in murine collagen-induced arthritis. Lab Invest. 2000 Aug;80(8):1195–1205. [PubMed]

Figures and Tables

Figure 1
Immunohistochemical staining of Ang-1 in RA and OA synovial tissue. (A) Ang-1 protein is demonstrated in RA synovial tissue in cells in the synovial lining layer, in some endothelial cells, and in cells within subsynovial tissue. (B) Isotype matched ...
Figure 2
In situ hybridisation for Ang-1 and Ang-2 in rheumatoid synovium. Ang-1 in situ hybridisation in synovial tissue samples from patients with RA using the Ang-1 antisense (A, C–F) and sense (B) probes, demonstrating representative areas of mRNA ...
Figure 3
Northern blot analysis of Ang-1 and Ang-2 in cultured synovial fibroblasts and human umbilical endothelial cells. (A) Induction of Ang-1 mRNA expression in cultured human synovial fibroblasts in response to TNFα (10 ng/ml) at baseline (lane 1) ...
Figure 4
ELISA analysis of Ang-1 protein in culture media of RA synovial fibroblasts. Ang-1 protein was quantified in the culture media of synovial fibroblasts stimulated with TNFα (10 ng/ml) at 0, 4, 18, 24, and 30 hours in this representative experiment. ...

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


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


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

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...