Cadherin-11 Provides Specific Cellular Adhesion between Fibroblast-like Synoviocytes

Valencia, Xavier; Higgins, Jonathan M.G.; Kiener, Hans P.; Lee, David M.; Podrebarac, Theresa; Dascher, Christopher C.; Watts, Gerald F.; Mizoguchi, Emiko; Simmons, Barry P.; Patel, Dhavalkumar D.; Bhan, Atul K.; Brenner, Michael B.

doi:10.1084/jem.20041545

Cited by 151 publications

(124 citation statements)

References 26 publications

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“…After the third passage, cells appeared fibroblast-like. Fluorescence-activated cell sorting (FACS) confirmed that the cells were negative for F4/80 and CD45 and positive for vascular cell adhesion molecule 1 (VCAM-1), suggesting that the cultures were FLS as previously described (4).…”

Section: Methodssupporting

confidence: 68%

“…Cadherin 11 has recently been identified on human and murine FLS and has been proposed to be a key mediator of synovial lining architecture and synovial inflammation (4)(5)(6). In the present study, we demonstrated that in addition to cadherin 11, FLS express a second mesenchymal cadherin, N-cadherin, but do not express the epithelial cadherin, E-cadherin.…”

Section: Discussionsupporting

confidence: 60%

“…Electron microscopic evaluation of the synovial lining has demonstrated that FLS form a loose cellular network within the ECM, with occasional apposed areas of cell-cell contact with other FLS and type A synoviocytes (1). The molecular basis of the intercellular contacts between FLS was unclear until the recent identification of cadherin 11 expression on human FLS (4). Human studies in vitro and murine studies in vivo have now established a critical role of cadherin 11 in the development and architecture of the synovium (5,6).…”

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confidence: 99%

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Coexpression of two mesenchymal cadherins, cadherin 11 and N‐cadherin, on murine fibroblast‐like synoviocytes

Agarwal

Lee

Kiener

et al. 2008

Arthritis & Rheumatism

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Objective. Cadherin 11 has recently been identified on fibroblast-like synoviocytes (FLS), and studies in mice have demonstrated its importance in synovial lining architecture and inflammation. However, many tissues express more than 1 cadherin. Given the newly appreciated functional significance of cadherins in the synovium, this study was undertaken to determine whether mouse FLS express other cadherins in addition to cadherin 11.Methods. The characterization of cadherin expression was determined in FLS derived from wild-type and cadherin 11-null mice using immunofluorescence (IF), biochemical, and immunohistologic techniques.Results. Cadherin 11 expression was observed at points of cell-cell contact in cultured wild-type mouse FLS. However, despite the lack of cell surface cadherin 11, cadherin 11-null mouse FLS cells still formed intimate cell-cell contacts that contained ␤-catenin. Immunoprecipitation of cell surface biotinylated FLS with anti-␤-catenin antibody demonstrated the presence of 2 cell surface catenin-associated proteins in FLS from wild-type mice and 1 in FLS sample from cadherin 11-null mice. Using biochemical approaches and reverse transcriptase-polymerase chain reaction, these proteins were determined to be N-cadherin and cadherin 11. Expression of both N-cadherin and cadherin 11 in the synovial lining was demonstrated by immunohistochemical analysis of mouse synovium. IF analyses demonstrated colocalization of N-cadherin and cadherin 11 to the same points of cell-cell contact. However, the inability to coimmunoprecipitate both cadherins using either anti-N-cadherin or anti-cadherin 11 antibodies suggests that these cadherins are not contained within the same molecular complexes.Conclusion. These findings demonstrate that FLS express both N-cadherin and cadherin 11, and suggest that these cadherins are not contained within the same molecular complex. Given their importance in modulating cellular behavior, understanding how these cadherins regulate FLS behavior individually and in concert will be critical to understanding synovial architecture and inflammation.

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Section: Methodssupporting

confidence: 68%

Section: Discussionsupporting

confidence: 60%

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confidence: 99%

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Coexpression of two mesenchymal cadherins, cadherin 11 and N‐cadherin, on murine fibroblast‐like synoviocytes

Agarwal

Lee

Kiener

et al. 2008

Arthritis & Rheumatism

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“…4A). Cadherin-11 is used by FLS in homotypic adhesive interactions, is expressed by synovial lining FLS, and is important for the overall morphology and development of the synovial lining (27). Monochromatic staining of B7-H3 or cadherin-11 showed almost identical patterns of expression.…”

Section: B7-h3 Is Broadly Expressed In Ra Synoviummentioning

confidence: 86%

Interactions of T Cells with Fibroblast-Like Synoviocytes: Role of the B7 Family Costimulatory Ligand B7-H3

Tran

Thacker

Louie

et al. 2008

The Journal of Immunology

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Fibroblast-like synoviocytes (FLS) and T cells can activate each other in vitro, and in vivo interactions between these cells may be important in rheumatoid arthritis (RA), yet FLS lack significant expression of CD28 ligands. We sought to identify molecules homologous to CD28 ligands that are strongly expressed by FLS, and documented strong B7-H3 expression on FLS and by fibroblasts of other tissues, which was unaffected by a variety of cytokines. Western blot analysis of FLS lysates showed predominant expression of the larger, four Ig-like domain isoform of B7-H3. Immunohistological sections of RA synovial tissue showed strong staining for B7-H3 on FLS. Cells expressing B7-H3 were distinct from but in close proximity to cells that expressed CD45, CD20, and CD3. Confocal microscopy of FLS and T cell cocultures showed localization of B7-H3 in the region of the T cell-FLS contact point, but distinct from the localization of T cell CD11a/CD18 (LFA-1) and FLS CD54 (ICAM-1). Reduction of B7-H3 expression on FLS by RNA interference affected interactions of FLS with resting T cells or cytokine-activated T cells. Resting T cells showed increased production of TNF-α, IFN-γ, and IL-2, whereas cytokine-activated T cells showed reduced cytokine production relative to control. However, cytokine production by T cells activated through their TCR was not notably altered by knock down of B7-H3. These observations suggest that B7-H3 may be important for the interactions between FLS and T cells in RA, as well as other diseases, and the outcome of such interactions depends on the activation state of the T cell.

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“…The homophilic interaction of FLS in synovial tissue was recently demonstrated to be mediated by cadherin 11, a classic cadherin that is primarily expressed by mesenchymal cells (19). Cadherins are a large family of transmembrane homodimeric proteins that are physically linked to the actin cytoskeleton via their cytoplasmic domain.…”

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Tumor necrosis factor α drives cadherin 11 expression in rheumatoid inflammation

Vandooren¹,

Cantaert²,

Borg³

et al. 2008

Arthritis & Rheumatism

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Objective. Cadherin 11 expressed on fibroblastlike synoviocytes (FLS) plays a key role in normal synovial architecture. The purpose of this study was to examine the expression of cadherin 11 in human synovitis.Methods. Cadherin 11 expression in synovial biopsy samples from patients with various types of arthritis and in lung biopsy samples from patients with interstitial pneumonitis (IP) was examined by immunostaining. The regulation of cadherin 11 expression in human FLS was assessed by quantitative reverse transcription-polymerase chain reaction analysis and Western blotting. Therapeutic modulation of synovial cadherin 11 was assessed before and after effective antiinflammatory therapy.Results. Abundant staining for cadherin 11 was seen in the intimal lining layer and the synovial sublining in inflamed tissues, with discrete staining in noninflammatory osteoarthritic (OA) tissues. The pattern and degree of immunostaining were similar in tissues from patients with rheumatoid arthritis (RA), nonpsoriatic spondylarthritis (SpA), psoriatic arthritis (PsA), and inflammatory OA. Clear staining for cadherin 11 was also observed in lung tissues from RA-associated IP and idiopathic IP patients, but was very limited in normal lung tissue. Cadherin 11 staining correlated strongly with the degree of inflammatory infiltration of the tissue, as well as with the C-reactive protein level and the erythrocyte sedimentation rate in RA patients. In vitro, cadherin 11 expression by FLS was consistently up-regulated by tumor necrosis factor ␣ (TNF␣) at the protein, but not the messenger RNA, level. Cadherin 11 staining in vivo was strongly down-regulated by prednisone treatment in RA patients and by TNF␣ blockade in SpA patients.Conclusion. Cadherin 11 expression is regulated by mediators of inflammation, such as TNF␣. Since cadherin 11 plays an important role in cartilage destruction in experimental arthritis, down-modulation of cadherin 11 by potent antiinflammatory therapies in humans with arthritis may contribute to halting cartilage damage.The synovial membrane, which encloses the joint cavity, consists of an intimal lining layer supported by the loose connective tissue of the synovial sublining. Under physiologic conditions, the intimal lining is composed of a few cell layers of apposing fibroblast-like synoviocytes (FLS) and CD68ϩ macrophage-like cells. In chronic arthritis, the intimal lining layer thickens to

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Cadherin-11 Provides Specific Cellular Adhesion between Fibroblast-like Synoviocytes

Cited by 151 publications

References 26 publications

Coexpression of two mesenchymal cadherins, cadherin 11 and N‐cadherin, on murine fibroblast‐like synoviocytes

Coexpression of two mesenchymal cadherins, cadherin 11 and N‐cadherin, on murine fibroblast‐like synoviocytes

Interactions of T Cells with Fibroblast-Like Synoviocytes: Role of the B7 Family Costimulatory Ligand B7-H3

Tumor necrosis factor α drives cadherin 11 expression in rheumatoid inflammation

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