Regulation of fibroblast response to IL-1 in rheumatoid arthritis by the transmembrane heparane sulfate proteoglycan syndecan-4
Final Report Abstract
Fibroblast-like synoviocytes from patients with rheumatoid arthritis (RA-FLS) exhibit an autonomously aggressive phenotype that is associated with the imprinting of important pathogenic features including an altered response to extracellular signals. In previous work that has led to this project, we had shown that the transmembrane heparan sulfate proteoglycan syndecan-4 (sdc4) is not only involved in the attachment of RA-FLS to cartilage, but also in the regulation of FLS responsiveness to cytokines, particulary interleukin-1 (IL-1). In this project we could substantiate out hypothesis that IL-1 directly binds to sdc4 and leads to its dimerization, which is independent of the IL-1 receptor 1 (IL-1R1). We could also demonstrate and mechanistically explain that and how, IL-1 induces the dimerization of sdc4 and that sdc4 regulates caveolin vesicle-mediated trafficking of the IL-1R1. We showed that in RA-FLS, the loss of sdc4 or the antibodymediated inhibition of sdc4 dimerization reduces the cell surface expression of the IL-1R and regulates the sensitivity of fibroblasts to IL-1. Administration of antibodies (Ab) against the dimerization domain of sdc4, thus, strongly reduced the expression IL1R1 on arthritic fibroblasts both in vitro and an animal model of human RA. In further and related work originating from this project, we could further strengthen the concept of sdc4 contributing to IL-1 meditated pathologies and identify novel Lasp1 as a novel interaction partner suggesting regulatory pathways of sdc4 involving cadherin-11 mediated cell-cell contacts.
Publications
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Syndecan-4 Modulates Epithelial Gut Barrier Function and Epithelial Regeneration in Experimental Colitis. Inflamm Bowel Dis. 2018 Nov 29;24(12):2579-2589
Fröhling M, …, Pap T, Stratis A, Bettenworth D
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Syndecan-4 Is Increased in Osteoarthritic Knee, but Not Hip or Shoulder, Articular Hypertrophic Chondrocytes. Cartilage. 2019 Aug 27:1947603519870855
Sanchez C, Lambert C, …, Pap T, Henrotin Y.
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Antibody-mediated inhibition of syndecan-4 dimerisation reduces interleukin (IL)-1 receptor trafficking and signalling. Ann Rheum Dis. 2020 Apr;79(4):481-489
Godmann L., Bollmann M., …, Pap T., Bertrand
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Lasp1 regulates adherens junction dynamics and fibroblast transformation in destructive arthritis. Nature Commun. 2021 Jun 15;12(1):3624
Beckmann D., Römer-Hillmann A., …, Pap T., Korb-Pap A.
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MMP-9 mediated Syndecan-4 shedding correlates with osteoarthritis severity. Osteoarthritis Cartilage. 2021 Feb;29(2):280-289
Bollmann M., …, Pap T., Stärke C., Lohmann C.H., Bertrand J.Bollmann M., …, Pap T.
