Differential expression and functional behaviour of the alpha v and beta 3 integrin subunits in cytokine stimulated fibroblast-like cells derived from synovial tissue of rheumatoid arthritis and osteoarthritis in vitro

Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) do not express the coxsackie-adenovirus (Ad) receptor and are poorly permissive to Ad serotype 5 (Ad5). Genetically modified, coxsackie-Ad receptor-independent Ad5 vectors were studied for gene delivery in human RA FLS and synovium explants and murine collagen-induced arthritis. Short-fiber Ad5 vectors with seven fiber shaft repeats Ad5GFP-R7-knob, Ad5GFP-R7-arginine-glycine-aspartic acid (RGD) (RGD-liganded), and Ad5GFPΔknob (knob-deleted) were compared with Ad5GFP-FiWT, a conventional wild-type (WT) Ad5 vector. Gene transfer by Ad5GFP-R7-knob and Ad5GFP-R7-RGD was 40- to 50-fold and 25-fold higher, respectively, than Ad5GFP-FiWT in FLS. Ad5GFPΔknob was more efficacious than its knob-bearing version Ad5GFP-R7-knob in FLS transduction. Virus attachment and entry required RGD- and LDV-binding integrins including αv, αvβ3, avβ5, and β1. Ad5GFP-R7-knob infection of FLS was partially neutralized by synovial fluid (SF), but remained 30- to 40-fold higher than Ad5GFP-FiWT in the presence of SF. Ad5GFPΔknob was partially neutralized by SF at low virus input, but escaped viral neutralization by SF at higher virus input. Gene transfer to human synovium ex vivo explants and murine collagen-induced arthritis in vivo was also more efficient with short fiber-modified vectors (with and without the knob domain) than Ad5GFPFiWT. Gene transfer by short fiber-modified vectors was enhanced by inflammatory cytokines in vitro and in the presence of inflammation in murine synovium in vivo. Our data indicated that the highly efficient gene delivery RA was mediated by RGD- and non-RGD-binding integrins and enhanced by inflammation. Short fiber modifications with knob ablation may be a strategy to enhance gene delivery, reducing vector dose and vector-induced inflammation and toxicity.

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“…Consistent with the literature (10,11,46), ␣ v ␤ 3 , ␣ v ␤ 5 , and ␣ v integrins were expressed in RA FLS as were ␣ 3 and ␤ 1 (Fig. 5A).…”

Section: Surface Expression and Role Of Integrin Receptors In Ad5gfp-supporting

confidence: 79%

“…This concept has been extended to disease-regulated therapeutic transgene expression (56 -58). Cytokines have been reported to downregulate ␣ v integrins in RA FLS and synovium (12,46). However, integrin expression levels do not correlate with Ad5-mediated transgene expression (13,59).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of Adenovirus-Mediated Gene Delivery to Rheumatoid Arthritis Synoviocytes and Synovium by Fiber Modifications: Role of Arginine-Glycine-Aspartic Acid (RGD)- and Non-RGD-Binding Integrins

Toh

Hong

Loo

et al. 2005

The Journal of Immunology

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“…RGD-binding integrins are highly expressed in the normal synovium. 9,10,12,13,19 We further evaluated the potential of the RGD-modified adenoviruses for transduction of the synovium by measuring the mRNA level for ␣ v in synovial cells. The ␣ v subunit was used as this subunit is most frequently present in RGD binding integrins.…”

Section: Discussionmentioning

confidence: 99%

“…The expression of RGD binding integrins is modulated in RA, for instance the ␣ v receptor is down-regulated, 10,11,13 and the ␣ 5 integrin is up-regulated. 19 The significance of the modulation for the RGD adenoviral trans- duction efficiency is not clear.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Dmitriev et al 8 have shown that introduction of the RGD motif in the HI loop of the fiber knob resulted in a CAR-independent cell entry via interaction with RGD binding integrins. 8 RGD binding integrins are highly expressed on synovium, [9][10][11][12][13] and could be better suited as receptors for adenoviral entry in synovial cells than the CAR. The only downside is that insertion of the RGD sequence for adenoviral entry will result in a broad tropism of the adenovirus.…”

Section: Introductionmentioning

confidence: 99%

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A tropism-modified adenoviral vector increased the effectiveness of gene therapy for arthritis

et al. 2001

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Integrin expression at the bone/biomaterial interface

Clarke

Revell

2001

J. Biomed. Mater. Res.

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The aim of this study was to visualize integrin expression by cells in interface tissue in relation to their ligands. Tissue samples were obtained from 25 patients undergoing revision of aseptically loose total joint replacements. Serial sections were immunolabeled for the integrins alpha(2)beta(1), alpha(v)beta(3), alpha(4)beta(1), alpha(L)beta(2) (CD11a), alpha(M)beta(2) (CD11b), and alpha(X)beta(2) (CD11c), and the ligands fibronectin, laminin, vitronectin, intercellular adhesion molecule-1, and vascular adhesion molecule-1. Most cells were found to express alpha(2)beta(1), most macrophages and giant cells expressed CD11b, and the majority of CD11a was found on perivascular T lymphocytes. From the small amount of alpha(4)beta(1) and vascular adhesion molecule-1 expression in the interface tissue and the combination of CD11a, CD11b, and intercellular adhesion molecule-1 expression, it would seem that macrophages use beta(2) integrins to transmigrate.

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Differential expression and functional behaviour of the alpha v and beta 3 integrin subunits in cytokine stimulated fibroblast-like cells derived from synovial tissue of rheumatoid arthritis and osteoarthritis in vitro

Cited by 27 publications

References 23 publications

Enhancement of Adenovirus-Mediated Gene Delivery to Rheumatoid Arthritis Synoviocytes and Synovium by Fiber Modifications: Role of Arginine-Glycine-Aspartic Acid (RGD)- and Non-RGD-Binding Integrins

Enhancement of Adenovirus-Mediated Gene Delivery to Rheumatoid Arthritis Synoviocytes and Synovium by Fiber Modifications: Role of Arginine-Glycine-Aspartic Acid (RGD)- and Non-RGD-Binding Integrins

A tropism-modified adenoviral vector increased the effectiveness of gene therapy for arthritis

Integrin expression at the bone/biomaterial interface

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