Cadherin 11 promotes invasive behavior of fibroblast‐like synoviocytes

Kiener, Hans P.; Niederreiter, Birgit; Lee, David M.; Jimenez-Boj, Esther; Smolen, Josef S.; Brenner, Michael B.

doi:10.1002/art.24453

Cited by 87 publications

(66 citation statements)

References 14 publications

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“…This amino acid motif matches the consensus sequence for the basophilic AGC kinases (such as protein kinase B), which regulate cell migration and whose activity is stimulated by integrin binding and interaction with T-cell receptors (21). C5orf30 sequences also contains a motif matching closely the consensus for CDK1 phosphorylation (amino acids [20][21][22][23][24][25][26][27][28][29][30], which coupled to recognition sequences for cyclins (amino acids 139-170) is a strong indication of a roles for C5orf30 in the cell cycle. C5orf30 encodes a basic polypeptide (pI 9.5), a feature typical of proteins interacting with phospholipids, membranes, and/or nucleic acid interactions.…”

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confidence: 69%

C5orf30 is a negative regulator of tissue damage in rheumatoid arthritis

Muthana

Hawtree

Wilshaw

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The variant rs26232, in the first intron of the chromosome 5 open reading frame 30 (C5orf30) locus, has recently been associated with both risk of developing rheumatoid arthritis (RA) and severity of tissue damage. The biological activities of human C5orf30 are unknown, and neither the gene nor protein show significant homology to any other characterized human sequences. The C5orf30 gene is present only in vertebrate genomes with a high degree of conservation, implying a central function in these organisms. Here, we report that C5orf30 is highly expressed in the synovium of RA patients compared with control synovial tissue, and that it is predominately expressed by synovial fibroblast (RASF) and macrophages in the lining and sublining layer of the tissue. These cells play a central role in the initiation and perpetuation of RA and are implicated in cartilage destruction. RASFs lacking C5orf30 exhibit increased cell migration and invasion in vitro, and gene profiling following C5orf30 inhibition confirmed up-regulation of genes involved in cell migration, adhesion, angiogenesis, and immune and inflammatory pathways. Importantly, loss of C5orf30 contributes to the pathology of inflammatory arthritis in vivo, because inhibition of C5orf30 in the collagen-induced arthritis model markedly accentuated joint inflammation and tissue damage. Our study reveal C5orf30 to be a previously unidentified negative regulator of tissue damage in RA, and this protein may act by modulating the autoaggressive phenotype that is characteristic of RASFs.

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mentioning

confidence: 69%

C5orf30 is a negative regulator of tissue damage in rheumatoid arthritis

Muthana

Hawtree

Wilshaw

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, cadherin-11 is expressed by fibroblasts in the lining layer, where it mediates homotypic synovial fibroblast adhesion. Overexpression of cadherin-11 in cultured RA synovial fibroblasts increases their invasiveness in vitro (20).…”

Section: Fibroblasts: Ubiquitous Cells With Regional Identitymentioning

confidence: 99%

Stromal Cells in Chronic Inflammation and Tertiary Lymphoid Organ Formation

Buckley

Barone

Nayar

et al. 2015

Annu. Rev. Immunol.

204

193

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Inflammation is an unstable state. It either resolves or persists. Why inflammation persists and the factors that define tissue tropism remain obscure. Increasing evidence suggests that tissue-resident stromal cells not only provide positional memory but also actively regulate the differential accumulation of inflammatory cells within inflamed tissues. Furthermore, at many sites of chronic inflammation, structures that mimic secondary lymphoid tissues are observed, suggesting that chronic inflammation and lymphoid tissue formation share common activation programs. Similarly, blood and lymphatic endothelial cells contribute to tissue homeostasis and disease persistence in chronic inflammation. This review highlights our increasing understanding of the role of stromal cells in inflammation and summarizes the novel immunological role that stromal cells exert in the persistence of inflammatory diseases.

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“…Sfib contribute to destructive arthritis by invasive proliferation (19) and are thus putative therapeutics targets in inflammatory arthritis (20). IPP-activated PB Vg9 + T cells from healthy individuals and scleroderma patients can disrupt fibroblast monolayers in vitro and induce fibroblast apoptosis partly mediated by TNF-a (15).…”

Section: Ipp-dependent Sfib Apoptosis Induced By Sfmc Vg9 + T Cellsmentioning

confidence: 99%

Cellular Interactions of Synovial Fluid γδ T Cells in Juvenile Idiopathic Arthritis

Bendersky

Marcu-Malina

Berkun

et al. 2012

The Journal of Immunology

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The pathogenesis of juvenile idiopathic arthritis (JIA) is thought to involve multiple components of the cellular immune system, including subsets of γδ T cells. In this study, we conducted experiments to define the functional roles of one of the major synovial fluid (SF) T cell subsets, Vγ9+Vδ2+ (Vγ9+) T cells, in JIA. We found that as opposed to CD4+ T cells, equally high percentages (∼35%) of Vγ9+ T cells in SF and peripheral blood (PB) produced TNF-α and IFN-γ. Furthermore, stimulation with isopentenyl pyrophosphate (IPP), a metabolite in the mevalonate pathway, which is a specific potent Ag for Vγ9Jγ1.2+ T cells, similarly amplified cytokine secretion by SF and PB Vγ9+ T cells. Significantly, the SF subset expressed higher levels of CD69 in situ, suggesting their recent activation. Furthermore, 24-h coculturing with SF-derived fibroblasts enhanced CD69 on the SF > PB Vγ9+ T cells, a phenomenon strongly augmented by zoledronate, a farnesyl pyrophosphate synthase inhibitor that increases endogenous intracellular IPP. Importantly, although Vγ9+ T cell proliferation in response to IPP was significantly lower in SF than PBMC cultures, it could be enhanced by depleting SF CD4+CD25+FOXP3+ cells (regulatory T cells). Furthermore, coculture with the Vγ9+ T cells in medium containing zoledronate or IPP strongly increased SF-derived fibroblasts' apoptosis. The findings that IPP-responsive proinflammatory synovial Vγ9+ T cells for which proliferation is partly controlled by regulatory T cells can recognize and become activated by SF fibroblasts and then induce their apoptosis suggest their crucial role in the pathogenesis and control of synovial inflammation.

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Cadherin 11 promotes invasive behavior of fibroblast‐like synoviocytes

Cited by 87 publications

References 14 publications

C5orf30 is a negative regulator of tissue damage in rheumatoid arthritis

C5orf30 is a negative regulator of tissue damage in rheumatoid arthritis

Stromal Cells in Chronic Inflammation and Tertiary Lymphoid Organ Formation

Cellular Interactions of Synovial Fluid γδ T Cells in Juvenile Idiopathic Arthritis

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