Regulation of the Angiopoietin-Tie ligand-receptor system with a novel splice variant of Tie1 reduces the severity of murine arthritis

Malik, Nasser; Pei, Jin; Raatz, Yvonne; Sumariwalla, Percy F.; Kiriakidis, Serafim; Shepard, Michael; Feldmann, Marc; Paleolog, Ewa

doi:10.1093/rheumatology/keq163

Cited by 19 publications

(13 citation statements)

References 42 publications

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“…A significant increase in transcript levels could be observed on day 8 for all genes, with mRNA levels gradually decreasing on day 12 (mean clinical score ± SEM of the analysed paws 1.67 ± 0.38), which is consistent with the array results. We have previously reported that expression of Ang-1 , Ang-2 , tyrosine kinase with immunoglobulin-like and EGF-like domains ( Tie )-1 and Tie-2 increases as arthritis progressed, peaking on day 8 of disease [33]. Of these, Ang-2 and Tie-2 showed modest changes (below 2-fold) on the array, whereas Ang-1 increased 2.7-fold on day 8 (Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…In a previous study we have shown that the expression of Ang-1 , Ang-2 , Tie-1 and Tie-2 mRNA is significantly higher in arthritic tissue of CIA mice, and that the application of a splice variant of TIE-1 ameliorates disease severity, reduces synovial vascularisation and bone destruction [33]. Our angiogenesis array identified Ang-1 as up-regulated by more than 2-fold, whereas Ang-2 was increased by only 1.6-fold on day 8 of CIA.…”

Section: Discussionmentioning

confidence: 99%

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Gene expression profiling and functional analysis of angiogenic markers in murine collagen-induced arthritis

et al. 2012

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IntroductionDysregulated angiogenesis is implicated in the pathogenesis of rheumatoid arthritis (RA). To provide a more profound understanding of arthritis-associated angiogenesis, we evaluated the expression of angiogenesis-modulating genes at onset, peak and declining phases of collagen-induced arthritis (CIA), a well-established mouse model for RA.MethodsCIA was induced in DBA/1 mice with type II collagen. Functional capillary density in synovial tissue of knee joints was determined by intravital fluorescence microscopy. To assess the ability of arthritic joint homogenates to induce angiogenesis, an endothelial chemotaxis assay and an in vivo matrigel plug assay were employed. The temporal expression profile of angiogenesis-related genes in arthritic paws was analysed by quantitative real-time RT-PCR using an angiogenesis focused array as well as gene specific PCR. Finally, we investigated the therapeutic effect of a monoclonal antibody specifically blocking the binding of VEGF to neuropilin (NRP)-1.ResultsAlthough arthritic paw homogenates displayed angiogenic activity in vitro and in vivo, and synovia of arthritic paws appeared highly vascularised on histological examination, the functional capillary density in arthritic knee synovia was significantly decreased, whereas capillary diameter was increased. Of the 84 genes analysed, 41 displayed a differential expression in arthritic paws as compared to control paws. Most significant alterations were seen at the peak of clinical arthritis. Increased mRNA expression could be observed for VEGF receptors (Flt-1, Flk-1, Nrp-1, Nrp-2), as well as for midkine, hepatocyte growth factor, insulin-like growth factor-1 and angiopoietin-1. Signalling through NRP-1 accounted in part for the chemotactic activity for endothelial cells observed in arthritic paw homogenates. Importantly, therapeutic administration of anti-NRP1B antibody significantly reduced disease severity and progression in CIA mice.ConclusionsOur findings confirm that the arthritic synovium in murine CIA is a site of active angiogenesis, but an altered balance in the expression of angiogenic factors seems to favour the formation of non-functional and dilated capillaries. Furthermore, our results validate NRP-1 as a key player in the pathogenesis of CIA, and support the VEGF/VEGF receptor pathway as a potential therapeutic target in RA.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Gene expression profiling and functional analysis of angiogenic markers in murine collagen-induced arthritis

et al. 2012

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“…Although Tie1 is important for embryonic vessel development, its expression is also increased during pathologic conditions in the adult (14)(15)(16). Recent studies have indicated expression of Tie1 in inflammatory tissue of rheumatoid arthritis and osteoarthritis patients (17,18). Additionally, overexpression of Tie1 augmented the inflammatory markers VCAM-1, ICAM-1, and E-selectin (19).…”

Section: Introductionmentioning

confidence: 99%

Tie1 attenuation reduces murine atherosclerosis in a dose-dependent and shear stress–specific manner

Woo¹,

Qu²,

Babaev³

et al. 2011

J. Clin. Invest.

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Although the response of endothelial cells to the disturbed blood flow in the vicinity of atherosclerotic lesions is known to be distinct from that elicited by nonatherogenic laminar flow, the mechanisms involved are poorly understood. Our initial studies confirmed that expression of the endothelial receptor tyrosine kinase Tie1 was evident at regions of atherogenic flow in mature animals. We therefore hypothesized that Tie1 plays a role in the endothelial response to atherogenic shear stress. Consistent with this, we found that Tie1 +/-mice bred to the apoE-deficient background displayed a 35% reduction in atherosclerosis relative to Tie1 +/+ ;Apoe -/-mice. Since deletion of Tie1 results in embryonic lethality secondary to vascular dysfunction, we used conditional and inducible mutagenesis to study the effect of endothelial-specific Tie1 attenuation on atherogenesis in Apoe -/-mice and found a dose-dependent decrease in atherosclerotic lesions. Analysis of primary aortic endothelial cells indicated that atheroprotective laminar flow decreased Tie1 expression in vitro. Attenuation of Tie1 was associated with an increase in eNOS expression and Tie2 phosphorylation. In addition, Tie1 attenuation increased IkBα expression while decreasing ICAM levels. In summary, we have found that shear stress conditions that modulate atherogenic events also regulate Tie1 expression. Therefore, Tie1 may play a novel proinflammatory role in atherosclerosis.

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“…5 8 22 23 Expression of Ang1, Ang2 and their receptor Tie2 are significantly increased in progression of collagen induced arthritis (CIA), and Tie2 blockade ameliorates bone destruction. 24 25 Recently, we demonstrated that Tie2 mediates Toll-like receptor-2 induced angiogenesis in Rheumatoid arthritis (RA). 26 The Notch signalling pathway plays a pivotal role in vascular development, cell-cell communication, cell fate decisions.…”

Section: Introductionmentioning

confidence: 99%

Notch signalling pathways mediate synovial angiogenesis in response to vascular endothelial growth factor and angiopoietin 2

et al. 2012

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ObjectiveNotch signalling pathways are critical for angiogenesis and endothelial cell (EC) fate; however the mechanisms regulating these processes in the inflamed joint remain to be elucidated. Here, we examine whether Notch signalling mediates vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2)-induced vascular function.MethodsNotch-1 intracellular domain (Notch-1 IC), Notch-4 IC, Delta-like-ligand 4, Hes-related transcriptional repressors-1 and 2 (Hrt-1, Hrt-2) mRNA and/or protein expression was measured by Real-time PCR and/or western blot. VEGF/Ang2 induced EC function was assessed using transwell invasion chambers, matrigel tube formation assays and wound repair scratch assays ± Notch-1 siRNA or an γ-secretase inhibitor N-(N-(3,5-Difluorophenacetyl-L-alanly))-S-phenylglycine-t-Butyl Ester (DAPT) in RA synovial explants or human microvascular EC. Interleukin (IL)-6 and IL-8 were measured by ELISA and MMP2 and 9 by gelatine zymography.ResultsNotch-1 IC and Notch-4 IC protein expressions were demonstrated in RA and psoriatic arthritis synovial biopsies, with minimal expression observed in Osteoarthritis (OA). VEGF and Ang2 induced Notch-1 IC/ Notch-4 IC protein expression in synovial explant cultures and human microvascular EC levels were further potentiated by VEGF/Ang2 stimulation in combination. Notch-1, Delta-like-ligand 4, and Hrt-2 mRNA expression were significantly induced by VEGF and Ang2 alone and in combination. Furthermore VEGF/Ang2-induced EC invasion, angiogenesis and migration were inhibited by Notch-1 siRNA or DAPT. Conditioned media from VEGF/Ang2 stimulated RA synovial explants induced EC tube formation, an effect that was inhibited by DAPT. Finally, DAPT significantly decreased VEGF/Ang2 induced IL-6, IL-8, MMP2 and 9 expressions in RA synovial explants.ConclusionsNotch-1 mediates VEGF/Ang2-induced angiogenesis and EC invasion in inflammatory arthritis.

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Regulation of the Angiopoietin-Tie ligand-receptor system with a novel splice variant of Tie1 reduces the severity of murine arthritis

Abstract: Our data demonstrate that the Ang-Tie ligand-receptor system is dysregulated in CIA. Tie1-751, a novel splice variant of the Tie1 receptor, inhibits Ang1/VEGF signalling, suggesting that Ang inhibition may be of therapeutic benefit in inflammatory arthritis.

Cited by 19 publications

References 42 publications

Gene expression profiling and functional analysis of angiogenic markers in murine collagen-induced arthritis

Gene expression profiling and functional analysis of angiogenic markers in murine collagen-induced arthritis

Tie1 attenuation reduces murine atherosclerosis in a dose-dependent and shear stress–specific manner

Notch signalling pathways mediate synovial angiogenesis in response to vascular endothelial growth factor and angiopoietin 2

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