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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2019

Open Access 01-12-2019 | Psoriatic Arthritis | Research article

Enhanced angiogenic function in response to fibroblasts from psoriatic arthritis synovium compared to rheumatoid arthritis

Authors: S. Fromm, C. C. Cunningham, M. R. Dunne, D. J. Veale, U. Fearon, S. M. Wade

Published in: Arthritis Research & Therapy | Issue 1/2019

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Abstract

Introduction

Angiogenesis is an early event in the pathogenesis of both psoriatic arthritis (PsA) and rheumatoid arthritis (RA); however, there are striking differences in blood vessel morphology and activation between the two arthropathies. The aim of this study was to assess if the PsA and RA joint microenvironments differentially regulate endothelial cell function.

Methods

PsA and RA primary synovial fibroblasts (SFC) were isolated from synovial biopsies, grown to confluence, and supernatants harvested and termed ‘conditioned media’ (CM). Human umbilical vein endothelial cells (HUVEC) were cultured with PsA SFC or RA SFC-CM (20%). HUVEC tube formation, migration, and PBMC adhesion were assessed by matrigel tube formation, wound repair, and PBMC adhesion assays. HUVEC cell surface expression of ICAM, VCAM, and E-Selectin was assessed by flow cytometry. Transcriptome analysis of genes promoting angiogenesis was performed by real-time PCR. Finally, a MSD multiplex angiogenic assay was performed on PsA SFC and RA SFC supernatants.

Results

Macroscopic synovitis and vascularity were similar in PsA and RA patients; however, significant differences in vascular morphological pattern were recorded with tortuous, elongated vessels observed in PsA compared to straight regular branching vessels observed in RA. Transcriptome analysis showed strong upregulation of the pro-angiogenic signature in HUVEC primed with PsA SFC-CM compared to RA SFC-CM and basal control. In parallel, paired PsA SFC-CM significantly induced HUVEC tube formation compared to that of RA SFC-CM. Furthermore, PsA SFC-CM induced HUVEC migration was paralleled by a significant induction in VEGFA, PFKFB3, ICAM-1, and MMP3 mRNA expression. A significant increase in PBMC adhesion and cell surface expression of VCAM-1, ICAM-1, and E-Selectin expression was also demonstrated in PsA SFC-CM-primed HUVEC compared to RA SFC-CM. Finally, VEGF, TSLP, Flt-1, and Tie-2 expression was elevated in PsA SFC-CM compared to RA SFC-CM, with no significant difference in other pro-angiogenic mediators including MIP-3, bFGF, PIGF, and MCP-1.

Conclusion

PsA SFC and RA SFC secreted factors differentially regulate endothelial cell function, with soluble mediators in the PsA joint microenvironment inducing a more pro-angiogenic phenotype compared to the RA.
Appendix
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Literature
1.
Koch AE. Angiogenesis as a target in rheumatoid arthritis. Ann Rheum Dis. 2003;62:60–7.CrossRef
2.
Reece RJ, Canete JD, Parsons WJ, Emery P, Veale DJ. Distinct vascular patterns of early synovitis in psoriatic, reactive, and rheumatoid arthritis. Arthritis Rheum. 1999;42:1481–4.PubMedCrossRef
3.
Fiocco U, Cozzi L, Chieco-Bianchi F, Rigon C, Vezzù M, Favero E, et al. Vascular changes in psoriatic knee joint synovitis. J Rheumatol. 2001;28:2480–6.PubMed
4.
Cañete JD, Rodríguez JR, Salvador G, Gómez-Centeno A, Muñoz-Gómez J, Sanmartí R. Diagnostic usefulness of synovial vascular morphology in chronic arthritis. A systematic survey of 100 cases. Semin Arthritis Rheum. 2003;32:378–87.PubMedCrossRef
5.
Baeten D, Keyser F De, Demetter P, Cuvelier C, Bosch F Van den, Kruithof E, et al. Comparative study of the synovial histology in rheumatoid arthritis, spondyloarthropathy, and osteoarthritis: influence of disease duration and activity. Ann Rheum Dis. 2000;59:945–53.PubMedPubMedCentralCrossRef
6.
Veale D, Yanni G, Rogers S, Barnes L, Bresnihan B, Fitzgerald O. Reduced synovial membrane macrophage numbers, ELAM-1 expression, and lining layer hyperplasia in psoriatic arthritis as compared with rheumatoid arthritis. Arthritis Rheum. 1993;36:893–900.PubMedCrossRef
7.
Fearon U, Griosios K, Fraser A, Reece R, Emery P, Jones PF, et al. Angiopoietins, growth factors, and vascular morphology in early arthritis. J Rheumatol. 2003;30:260–8.PubMed
8.
Elshabrawy HA, Chen Z, Volin MV, Ravella S, Virupannavar S, Shahrara S. The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis. 2015;18(4):433–48.PubMedPubMedCentralCrossRef
9.
Fearon U, Reece R, Smith J, Emery P, Veale DJ. Synovial cytokine and growth factor regulation of MMPs/TIMPs: implications for erosions and angiogenesis in early rheumatoid and psoriatic arthritis patients. Ann N Y Acad Sci. 1999;878:619–21.PubMedCrossRef
10.
Cañete JD, Pablos JL, Sanmartí R, Mallofré C, Marsal S, Maymó J, Gratacós J, Mezquita J, Mezquita C, Cid MC. Antiangiogenic effects of anti-tumor necrosis factor alpha therapy with infliximab in psoriatic arthritis. Arthritis Rheum. 2004;50:1636–41.PubMedCrossRef
11.
Ahmed SF, Attia EA, Saad AA, Sharara M, Fawzy H, El Nahrery EM. Serum YKL-40 in psoriasis with and without arthritis; correlation with disease activity and high-resolution power Doppler ultrasonographic joint findings. J Eur Acad Dermatol Venereol. 2015;29:682–8.PubMedCrossRef
12.
Dakin SG, Coles M, Sherlock JP, Powrie F, Carr AJ, Buckley CD. Pathogenic stromal cells as therapeutic targets in joint inflammation. Nat Rev Rheumatol. 2018;14:714–26.PubMedCrossRef
13.
Balogh E, Veale DJ, McGarry T, Orr C, Szekanecz Z, Ng C-T, et al. Oxidative stress impairs energy metabolism in primary cells and synovial tissue of patients with rheumatoid arthritis. Arthritis Res Ther. 2018;20:95.PubMedPubMedCentralCrossRef
14.
Wade SM, Trenkmann M, McGarry T, Canavan M, Marzaioli V, Wade SC, et al. Altered expression of microRNA-23a in psoriatic arthritis modulates synovial fibroblast pro-inflammatory mechanisms via phosphodiesterase 4B. J Autoimmun. 2019;96:86–93.PubMedCrossRef
15.
Müller-Ladner U, Kriegsmann J, Franklin BN, Matsumoto S, Geiler T, Gay RE, et al. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am J Pathol. 1996;149:1607–15.PubMedPubMedCentral
16.
Xue M, McKelvey K, Shen K, Minhas N, March L, Park S-Y, et al. Endogenous MMP-9 and not MMP-2 promotes rheumatoid synovial fibroblast survival, inflammation and cartilage degradation. Rheumatology. 2014;53:2270–9.PubMedCrossRef
17.
Kim HY, Park SY, Lee SW, Lee HR, Lee WS, Rhim BY, et al. Inhibition of HMGB1-induced angiogenesis by cilostazol via SIRT1 activation in synovial fibroblasts from rheumatoid arthritis. Bursill C, ed. PLoS One. 2014;9:e104743.
18.
Lu Y, Yu S-S, Zong M, Fan S-S, Lu T-B, Gong R-H, et al. Glucose-6-phosphate isomerase (G6PI) mediates hypoxia-induced angiogenesis in rheumatoid arthritis. Sci Rep. 2017;7:40274.PubMedPubMedCentralCrossRef
19.
del Rey MJ, Izquierdo E, Caja S, Usategui A, Santiago B, Galindo M, et al. Human inflammatory synovial fibroblasts induce enhanced myeloid cell recruitment and angiogenesis through a hypoxia-inducible transcription factor 1α/vascular endothelial growth factor-mediated pathway in immunodeficient mice. Arthritis Rheum. 2009;60:2926–34.PubMedCrossRef
20.
McGarry T, Veale DJ, Gao W, Orr C, Fearon U, Connolly M. Toll-like receptor 2 (TLR2) induces migration and invasive mechanisms in rheumatoid arthritis. Arthritis Res Ther. 2015;17:153.PubMedPubMedCentralCrossRef
21.
Huang M, Qiu Q, Zeng S, Xiao Y, Shi M, Zou Y, et al. Niclosamide inhibits the inflammatory and angiogenic activation of human umbilical vein endothelial cells. Inflamm Res. 2015;64:1023–32.PubMedCrossRef
22.
Szekanecz Z, Pakozdi A, Szentpetery A, Besenyei T, Koch AE. Chemokines and angiogenesis in rheumatoid arthritis. Front Biosci. 2009;1:44–51.
23.
Scott BB, Zaratin PF, Colombo A, Hansbury MJ, Winkler JD, Jackson JR. Constitutive expression of angiopoietin-1 and -2 and modulation of their expression by inflammatory cytokines in rheumatoid arthritis synovial fibroblasts. J Rheumatol. 2002;29:230–9.PubMed
24.
Saber T, Veale DJ, Balogh E, McCormick J, NicAnUltaigh S, Connolly M, et al. Toll-like receptor 2 induced angiogenesis and invasion is mediated through the Tie2 signalling pathway in rheumatoid arthritis. PLoS One. 2011;6:e23540.PubMedPubMedCentralCrossRef
25.
Honorati MC, Neri S, Cattini L, Facchini A. Interleukin-17, a regulator of angiogenic factor release by synovial fibroblasts. Osteoarthr Cartil. 2006;14:345–52.CrossRef
26.
Cho M-L, Ju J-H, Kim H-R, Oh H-J, Kang C-M, Jhun J-Y, et al. Toll-like receptor 2 ligand mediates the upregulation of angiogenic factor, vascular endothelial growth factor and interleukin-8/CXCL8 in human rheumatoid synovial fibroblasts. Immunol Lett. 2007;108:121–8.PubMedCrossRef
27.
Ritchlin C, Haas-Smith SA, Hicks D, Cappuccio J, Osterland CK, Looney RJ. Patterns of cytokine production in psoriatic synovium. J Rheumatol. 1998;25:1544–52.PubMed
28.
Gao W, Sweeney C, Walsh C, Rooney P, McCormick J, Veale DJ, et al. Notch signalling pathways mediate synovial angiogenesis in response to vascular endothelial growth factor and angiopoietin 2. Ann Rheum Dis. 2013;72:1080–8.PubMedCrossRef
29.
Gao W, Sweeney C, Connolly M, Kennedy A, Ng CT, McCormick J, et al. Notch-1 mediates hypoxia-induced angiogenesis in rheumatoid arthritis. Arthritis Rheum. 2012;64:2104–13.PubMedCrossRef
30.
Clem B, Telang S, Clem A, Yalcin A, Meier J, Simmons A, et al. Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Mol Cancer Ther. 2008;7:110–20.PubMedCrossRef
31.
Chesney J, Mitchell R, Benigni F, Bacher M, Spiegel L, Al-Abed Y, et al. An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect. Proc Natl Acad Sci U S A. 1999;96:3047–52.PubMedPubMedCentralCrossRef
32.
De Bock K, Wong BW, Cantelmo AR, Quaegebeur A, Ghesquiè Re B, Cauwenberghs S, et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell. 2013;154:651–63.PubMedCrossRef
33.
Cantelmo AR, Conradi L-C, Brajic A, Goveia J, Kalucka J, Pircher A, et al. Inhibition of the glycolytic activator PFKFB3 in endothelium induces tumor vessel normalization, impairs metastasis, and improves chemotherapy. Cancer Cell. 2016;30:968–85.PubMedPubMedCentralCrossRef
34.
Goedkoop AY, Kraan MC, Picavet DI, de Rie MA, Teunissen MBM, Bos JD, et al. Deactivation of endothelium and reduction in angiogenesis in psoriatic skin and synovium by low dose infliximab therapy in combination with stable methotrexate therapy: a prospective single-centre study. Arthritis Res Ther. 2004;6:R326–34.PubMedPubMedCentralCrossRef
35.
Kennedy A, Ng CT, Chang TC, Biniecka M, O’Sullivan JN, Heffernan E, et al. Tumor necrosis factor blocking therapy alters joint inflammation and hypoxia. Arthritis Rheum. 2011;63:923–32.PubMedCrossRef
36.
Markham T, Mullan R, Golden-Mason L, Rogers S, Bresnihan B, FitzGerald O, et al. Resolution of endothelial activation and down-regulation of Tie2 receptor in psoriatic skin after infliximab therapy. J Am Acad Dermatol. 2006;54:1003–12.PubMedCrossRef
37.
Ramírez J, Inciarte-Mundo J, Cuervo A, Ruiz-Esquide V, Hernández MV, Sanmartí R, et al. Differing local and systemic inflammatory burden in polyarticular psoriatic arthritis and rheumatoid arthritis patients on anti-TNF treatment in clinical remission. Clin Exp Rheumatol. 2017;35:74–9.PubMed
38.
Cordiali-Fei P, Trento E, D'Agosto G, Bordignon V, Mussi A, Ardigó M, et al. Effective therapy with anti-TNF-alpha in patients with psoriatic arthritis is associated with decreased levels of metalloproteinases and angiogenic cytokines in the sera and skin lesions. Ann N Y Acad Sci. 2007;1110:578–89.PubMedCrossRef
39.
40.
Pierer M, Rethage J, Seibl R, Lauener R, Brentano F, Wagner U, et al. Chemokine secretion of rheumatoid arthritis synovial fibroblasts stimulated by Toll-like receptor 2 ligands. J Immunol. 2004;172:1256–65.PubMedCrossRef
41.
Dong J, Grunstein J, Tejada M, Peale F, Frantz G, Liang W-C, et al. VEGF-null cells require PDGFR α signaling-mediated stromal fibroblast recruitment for tumorigenesis. EMBO J. 2004;23:2800–10.PubMedPubMedCentralCrossRef
42.
Frank-Bertoncelj M, Trenkmann M, Klein K, Karouzakis E, Rehrauer H, Bratus A, et al. Epigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions. Nat Commun. 2017;8:14852.PubMedPubMedCentralCrossRef
43.
Croft AP, Campos J, Jansen K, Turner JD, Marshall J, Attar M, et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature. 2019;570:246–51.PubMedPubMedCentralCrossRef
44.
Xie F, Meng Y-H, Liu L-B, Chang K-K, Li H, Li M-Q, et al. Cervical carcinoma cells stimulate the angiogenesis through TSLP promoting growth and activation of vascular endothelial cells. Am J Reprod Immunol. 2013;70:69–79.PubMedCrossRef
45.
Zhang B, Wei C, Chang K, Yu J, Zhou W, Yang H, et al. TSLP promotes angiogenesis of human umbilical vein endothelial cells by strengthening the crosstalk between cervical cancer cells and eosinophils. Oncol Lett. 2017;14:7483–8.PubMedPubMedCentral
46.
Yu X, Peng Y, Liang H, Fu K, Zhao Z, Xie C, et al. TSLP/TSLPR promote angiogenesis following ischemic stroke via activation of the PI3K/AKT pathway. Mol Med Rep. 2017;17:3411–7.PubMed
47.
Moret FM, Hack CE, van der Wurff-Jacobs KM, Lafeber FP, van Roon JA. TSLP: a novel potent proinflammatory mediator that activates myeloid dendritic cells to stimulate Th1 and Th17 activity in rheumatoid arthritis. Ann Rheum Dis. 2011;70:A43–4.CrossRef
48.
Hartgring SAY, Willis CR, Dean CE, Broere F, van Eden W, Bijlsma JWJ, et al. Critical proinflammatory role of thymic stromal lymphopoietin and its receptor in experimental autoimmune arthritis. Arthritis Rheum. 2011;63:1878–87.PubMedCrossRef
49.
Marton N, Kovács OT, Baricza E, Kittel Á, Győri D, Mócsai A, et al. Extracellular vesicles regulate the human osteoclastogenesis: divergent roles in discrete inflammatory arthropathies. Cell Mol Life Sci. 2017;74:3599–611.PubMedCrossRef
50.
51.
Zhang HG, Liu C, Su K, Yu S, Zhang L, Zhang S, et al. A membrane form of TNF-alpha presented by exosomes delays T cell activation-induced cell death. J Immunol. 2006;176:7385–93.PubMedCrossRef
52.
Kato T, Miyaki S, Ishitobi H, Nakamura Y, Nakasa T, Lotz MK, et al. Exosomes from IL-1β stimulated synovial fibroblasts induce osteoarthritic changes in articular chondrocytes. Arthritis Res Ther. 2011;16:R163.CrossRef
53.
Kennedy A, Ng CT, Biniecka M, Saber T, Taylor C, O'Sullivan J, et al. Angiogenesis and blood vessel stability in inflammatory arthritis. Arthritis Rheum. 2010;62:711–21.PubMedCrossRef
Metadata
Title
Enhanced angiogenic function in response to fibroblasts from psoriatic arthritis synovium compared to rheumatoid arthritis
Authors
S. Fromm
C. C. Cunningham
M. R. Dunne
D. J. Veale
U. Fearon
S. M. Wade
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2019
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-019-2088-3

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