Expression of Notch homologues in the synovium of rheumatoid arthritis and osteoarthritis patients

Ishii, Hidetoki; Nakazawa, Minako; Yoshino, Shinichi; Nakamura, Hiroshi; Nishioka, Kusuki; Nakajima, Takeshi

doi:10.1007/s002960100119

Cited by 32 publications

(19 citation statements)

References 20 publications

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“…This diversity may be due to the different stimulation concentration of TNF- α used in experimental system or the different culture times. Indeed, the expression profile of Notch receptors or ligands in RA local synovium tissue also varied among previous reports [7, 8, 11]. Nevertheless, here we confirmed the result that TNF- α could induce the activation of Notch signaling in cultured RA FLSs.…”

Section: Discussionsupporting

confidence: 88%

“…Ishii et al and Yabe et al showed that the expression pattern of Notch homologues among synovium from OA and RA patients differed from that of normal subjects [7, 8]. Another report demonstrated the expression of Notch-1 in synoviocytes and the presence of Notch-1 fragment in the nuclei of RA synoviocytes and suggested the involvement of Notch-1 signaling in the TNF- α -induced proliferation of RA synoviocytes [9].…”

Section: Introductionmentioning

confidence: 99%

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Notch Signaling Mediates TNF-α-Induced IL-6 Production in Cultured Fibroblast-Like Synoviocytes from Rheumatoid Arthritis

Jiao

Wang

et al. 2012

Clinical and Developmental Immunology

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It has been reported that Notch family proteins are expressed in synovium tissue and involved in the proliferation of synoviocyte from rheumatoid arthritis (RA). The aim of this paper was to investigate whether Notch signaling mediated TNF-α-induced cytokine production of cultured fibroblast-like synoviocytes (FLSs) from RA. Exposure of RA FLSs to TNF-α (10 ng/ml) led to increase of Hes-1, a target gene of Notch signaling, and a marked upregulation of Notch 2, Delta-like 1, and Delta-like 3 mRNA levels. Blockage of Notch signaling by a γ-secretase inhibitor (DAPT) inhibited IL-6 secretion of RA FLSs in response to TNF-α while treatment with recombinant fusion protein of Notch ligand Delta-like 1 promoted such response. TNF-α stimulation also induced IL-6 secretion in OA FLSs; however, the Hes-1 level remained unaffected. Our data confirm the functional involvement of Notch pathway in the pathophysiology of RA FLSs which may provide a new target for RA therapy.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Notch Signaling Mediates TNF-α-Induced IL-6 Production in Cultured Fibroblast-Like Synoviocytes from Rheumatoid Arthritis

Jiao

Wang

et al. 2012

Clinical and Developmental Immunology

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“…It has also been shown that there is a high level of expression of DLL-1, Jagged-1, Notch-1, Notch-2 and Notch-3 in the synovium of RA patients 9 41. However, the precise role of each Notch ligand in autoimmune diseases remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Notch signalling ameliorates experimental inflammatory arthritis

Park

Kim

et al. 2013

Ann Rheum Dis

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ObjectiveTo test the hypothesis that Notch signalling plays a role in the pathogenesis of rheumatoid arthritis (RA) and to determine whether pharmacological inhibition of Notch signalling with γ-secretase inhibitors can ameliorate the RA disease process in an animal model.MethodsCollagen-induced arthritis was induced in C57BL/6 or Notch antisense transgenic mice by immunisation with chicken type II collagen (CII). C57BL/6 mice were administered with different doses of inhibitors of γ-secretase, an enzyme required for Notch activation, at disease onset or after onset of symptoms. Severity of arthritis was monitored by clinical and histological scores, and in vivo non-invasive near-infrared fluorescence (NIRF) images. Micro-CT was used to confirm joint destruction. The levels of CII antibodies and cytokines in serum were determined by ELISA and bead-based cytokine assay. The expression levels of cytokines were studied by quantitative PCR in rheumatoid synovial fibroblasts.ResultsThe data show that Notch signalling stimulates synoviocytes and accelerates their production of proinflammatory cytokines and immune responses involving the upregulation of IgG1 and IgG2a. Pharmacological inhibition of γ-secretase and antisense-mediated knockdown of Notch attenuates the severity of inflammatory arthritis, including arthritis indices, paw thickness, tissue damage and neutrophil infiltration, and reduces the levels of active NF-κB, ICAM-1, proinflammatory cytokines and matrix metalloproteinase-3 activity in the mouse model of RA.ConclusionsThese results suggest that Notch is involved in the pathogenesis of RA and that inhibition of Notch signalling is a novel approach for treating RA.

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“…Notably, blockade of Dll1, as well as Jagged1, did not affect the parameters of bone strength and structure in the absence of any stimulation as shown in sham-operated mice. A high expression of Dll1 and Jagged1 as well as Notch1, Notch2 and Notch3 has been demonstrated in the synovium of RA patients [30,31]. We previously demonstrated that Dll1 was expressed on a part of the macrophage population and that inflammatory cytokines, such as tumor nuclear factor-alpha or interferon-gamma, induced the expression of Dll1 on macrophages [9].…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of osteoclastogenesis by Notch2/Delta-like 1 and Notch1/Jagged1 axes

et al. 2012

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IntroductionOsteoclastogenesis plays an important role in the bone erosion of rheumatoid arthritis (RA). Recently, Notch receptors have been implicated in the development of osteoclasts. However, the responsible Notch ligands have not been identified yet. This study was undertaken to determine the role of individual Notch receptors and ligands in osteoclastogenesis.MethodsMouse bone marrow-derived macrophages or human peripheral blood monocytes were used as osteoclast precursors and cultured with receptor activator of nuclear factor-kappaB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF) to induce osteoclasts. Osteoclasts were detected by tartrate-resistant acid phosphatase (TRAP) staining. K/BxN serum-induced arthritic mice and ovariectomized mice were treated with anti-mouse Delta-like 1 (Dll1) blocking monoclonal antibody (mAb).ResultsBlockade of a Notch ligand Dll1 with mAb inhibited osteoclastogenesis and, conversely, immobilized Dll1-Fc fusion protein enhanced it in both mice and humans. In contrast, blockade of a Notch ligand Jagged1 enhanced osteoclastogenesis and immobilized Jagged1-Fc suppressed it. Enhancement of osteoclastogenesis by agonistic anti-Notch2 mAb suggested that Dll1 promoted osteoclastogenesis via Notch2, while suppression by agonistic anti-Notch1 mAb suggested that Jagged1 suppressed osteoclastogenesis via Notch1. Inhibition of Notch signaling by a gamma-secretase inhibitor suppressed osteoclastogenesis, implying that Notch2/Dll1-mediated enhancement was dominant. Actually, blockade of Dll1 ameliorated arthritis induced by K/BxN serum transfer, reduced the number of osteoclasts in the affected joints and suppressed ovariectomy-induced bone loss.ConclusionsThe differential regulation of osteoclastogenesis by Notch2/Dll1 and Notch1/Jagged1 axes may be a novel target for amelioration of bone erosion in RA patients.

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Expression of Notch homologues in the synovium of rheumatoid arthritis and osteoarthritis patients

Cited by 32 publications

References 20 publications

Notch Signaling Mediates TNF-α-Induced IL-6 Production in Cultured Fibroblast-Like Synoviocytes from Rheumatoid Arthritis

Notch Signaling Mediates TNF-α-Induced IL-6 Production in Cultured Fibroblast-Like Synoviocytes from Rheumatoid Arthritis

Inhibition of Notch signalling ameliorates experimental inflammatory arthritis

Differential regulation of osteoclastogenesis by Notch2/Delta-like 1 and Notch1/Jagged1 axes

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