Angiogenesis markers (VEGF, soluble receptor of VEGF and angiopoietin-1) in very early arthritis and their association with inflammation and joint destruction

doi:10.1016/j.clim.2007.04.014

Clinical Immunology

Volume 124, Issue 2, August 2007, Pages 158-164

https://doi.org/10.1016/j.clim.2007.04.014 Get rights and content

Abstract

Objective:

To investigate the involvement of angiogenesis markers in very early arthritis patients and their relevance to predict further joint destruction.

Methods:

Levels of Vascular Endothelial Growth Factor (VEGF), angiopoietin-1 (Ang-1), and soluble Fms-like tyrosine kinase-1 (sFlt-1) were measured by ELISA in serum samples from 310 patients having polyarthritis, evolving for less than 6 months (VErA cohort). Each angiogenesis marker was measured at baseline and one year later. X-rays of hands and feet were carried out at inclusion and after 1 year and read using the van der Heidje-modified Sharp method.

Results:

At baseline and after 1 year, VEGF levels were correlated with clinical and biological parameters of inflammation. We also observed a positive correlation between sFlt-1 levels and biological inflammation (Erythrocyte Sedimentation Rate (ESR): r = 0.17, p = 0.006; C Reactive Protein: r = 0.14, p = 0.02). Angiopoietin-1 levels were correlated with ESR (r = 0.12, p = 0.04). Interestingly, only VEGF levels measured at baseline were correlated with Disease Activity Score measured 1 year later.

Relationship between angiogenesis markers and radiographic progression was also evaluated. VEGF and Ang-1 levels measured at inclusion were related with Sharp score after one year (VEGF: r = 0.21, p < 0.001; Ang-1: r = 0.24, p < 0.001; Spearman's test). Moreover, VEGF levels were higher in patients with radiographic progression (p = 0.002).

Conclusion:

Serum concentrations of VEGF, sFlt-1 and angiopoietin-1 were correlated to parameters of inflammation and to bone destruction in early arthritis. These results contribute to demonstrate that angiogenesis reflects disease severity and angiogenesis markers might become a new useful tool to evaluate disease activity and to estimate outcome for patients with inflammatory arthritis.

Section snippets

Patients

The VErA project is an inceptive community-based cohort which comprises 310 patients with early inflammatory arthritis prospectively recruited between October 1988 and January 2002, in two French regions, i.e., entire province of the Upper Normandy (1,800,000 people) and metropolitan area of Amiens (300,000 people). All private rheumatologists and those running rheumatology clinics in the 5 hospitals of this area were contacted for this project. All these physicians were encouraged to notify

Relationship between angiogenesis (VEGF, VEGFR-1, Ang-1) and inflammatory parameters at inclusion and after one year

Clinical and biological inflammatory parameters are shown for all patients in Table 1. VEGF, VEGFR-1 and Ang-1 were evaluated in serum from every patient with very early arthritis by ELISA (Table 2 and Fig. 1). For VEGF measurement, our data at baseline are very similar to those shown by Ballara et al. [18] in inflammatory arthritis. Clinical inflammation, evaluated by swollen joint count, Ritchie index and by Disease Activity Score (DAS), was correlated with VEGF levels. At inclusion, the

Discussion

This work studied three angiogenesis markers in patients with inflammatory arthritis and their relationship with joint destruction evaluated by radiographic progression. All angiogenesis markers studied were correlated to disease activity and to inflammatory parameters. Our results, obtained from 310 patients with very early arthritis, confirmed that angiogenesis markers, mainly VEGF, are increased in patients with radiographic progression. The two proangiogenic parameters, VEGF and Ang-1, also

Acknowledgments

This study was granted by the Fondation de la Recherche Médicale et by French ministry of Health (Programme Hospitalier de Recherche Clinique 1997).

The authors are grateful to the Société Française de Rhumatologie (SFR) for their financial support.

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The flavonoids monomers in Daphne Genkwa were separated by preparative liquid chromatography and identified by HPLC-ESI-ITMS. An in vitro inflammatory model of macrophage RAW264.7 induced by LPS and an angiogenesis model of human umbilical vein endothelial cells induced by TNF-α were established. Flavonoids were extracted and prepared for intervention to detect the amount of secretion after drug intervention to reflect the anti-inflammatory and anti-angiogenic activities of each component. In addition, a new mathematical method, which combined principal component analysis and efficacy coefficient method, was adopted in pharmacodynamic evaluation.
Fourteen flavonoids monomers were separated by preparative liquid chromatography and identified by HPLC-ESI-ITMS including H1 (hydroxygenkwanin-5-O-β-D-glucoside), H2 (apigenin-7-O-β-D-glucoside), H3 (kaempferol-3-O-β-D-glucoside), H4 (hydroxygenkwanin-5-O-β-D-primeveroside), H5 (apigenin-5-O-β-D-primeveroside), H6 (apigenin-7-O-β-D-glucuronide), H7 (luteolin-5-O-β-D-glucopyranoside), H8 (genkwain-5-O-β-D- glucoside), H9 (luteolin), H10 (Daphnodorin G), H11 (tiliroside), H12 (apigenin), H13 (3′- hydroxygenkwain) and H14 (genkwanin). We found that most of flavonoids down-regulated VCAM and MMP-3, while H1, H8, H9, H14 reduced VEGF and ICAM was only decreased by H14.
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Angiogenesis markers (VEGF, soluble receptor of VEGF and angiopoietin-1) in very early arthritis and their association with inflammation and joint destruction

Abstract

Objective:

Methods:

Results:

Conclusion:

Section snippets

Patients

Relationship between angiogenesis (VEGF, VEGFR-1, Ang-1) and inflammatory parameters at inclusion and after one year

Discussion

Acknowledgments

Trends Pharmacol. Sci.

Jt. Bone Spine

Best Pract. Res., Clin. Rheumatol.

Life Sci.

Lancet

Clinical applications of angiogenic growth factors and their inhibitors

Nat. Med.

Angiogenesis in cancer, vascular, rheumatoid and other disease