Artikel
Integrin α11β1 deficiency affects joint destructions in arthritic hTNFtg mice
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Veröffentlicht: | 8. Oktober 2019 |
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Gliederung
Text
Background: Integrins are connectors between the extracellular matrix (ECM) and intracellular signalling pathways involved in the regulation of cellular proliferation, migration, tissue invasion, cytokine and MMP production – key mechanisms leading to joint destruction during rheumatoid arthritis (RA). In this context, integrin α11β1 (ITGA11) is of special interest, because it is mainly expressed in cellular adhesive structures of mesenchymal cells. In this project we investigated the role of ITGA11 in the development of joint destructions in hTNFtg mice, an animal model resembling the arthritic pathology of human RA.
Methods: ITGA11 expression levels in SF of wild type (wt) and arthritic hTNFtg mice were analysed by Western Blot (WB) and immunofluorescence as well as immunohistochemistry using paraffin-embedded hind paws. Furthermore, different ECM substrates and their influence on ITGA11 expression and its subcellular location as well as expression pattern of interaction partners (e.g. vinculin, paxillin and talin) were investigated using WB and immunofluorescence. In functional studies isolated SF of ITGA11-/- mice were analysed regarding to invasiveness using a modified TEER-Assay and to identify coating-dependent differences in migration and adhesion.
Furthermore, ITGA11-/- mice were interbred with hTNFtg mice and arthritis parameters and histomorphological changes of the offspring were analysed by evaluation of clinical symptoms, µCT imaging and histopathology.
Results: hTNFtg SF showed a coating-independent enrichment of focal adhesions with an increased and most prominent expression of ITGA11. Coatings such as collagen I or fibronectin resulted in different expression levels of vinculin, paxillin and talin, but any differences between wt and ITGA11-/- SF were detectable. Analyses of the functional assays showed a reduced proliferation rate and invasiveness of ITGA11-/- SF, an altered coating-dependent migration rate and adhesion capacity of ITGA11-/- SF in comparison to wt SF. In vivo evaluation of ITGA11-/-hTNFtg mice revealed a milder arthritis score and less cartilage and bone destructions compared to hTNFtg mice.
Conclusion: ITGA11 is significantly up-regulated in hTNFtg mice and is involved in the pathological processes of cartilage and bone destructions during RA.