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Holmdahl, Rikard

doi:10.1186/ar82

Cited by 11 publications

(1 citation statement)

References 65 publications

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“…Our study identified RB1 mRNA as a direct target of miR-199a-3p. Mutation or aberrant expression of oncogene and tumor suppressor genes, such as TP53, have been shown in RA-FLS, but their role on RA pathophysiology has been unclear and controversial [ 24 ]. Our results provided direct functional relevance of RB1 in RA-FLS: it promotes RA-FLS proliferation and inhibits RA-FLS apoptosis, an effect that was under direct regulation of miR-199a-3p.…”

Section: Discussionmentioning

confidence: 99%

MiR-199a-3p inhibits proliferation and induces apoptosis in rheumatoid arthritis fibroblast-like synoviocytes via suppressing retinoblastoma 1

Wangyang

Wang

et al. 2018

Bioscience Reports

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Background Fibroblast-like synoviocytes (FLSs) that line the intimal synovium play a crucial role in the pathogenesis of rheumatoid arthritis (RA). miR-199a-3p is a highly conserved miRNA that has been shown to regulate a variety of growth behaviors in diverse cell types. However, the role of miR-199a-3p in RA-FLS is still unknown. Methods Here, we presented the first experimental evidence showing that miR-199a-3p was a critical regulator of RA-FLS function. Results miR-199a-3p expression was significantly reduced in RA-FLS compared with normal FLS. Ectopic expression of miR-199a-3p significantly inhibited RA-FLS proliferation and induced apoptosis, which was demonstrated by an increase in caspase-3 activity and Bax/Bcl-2 ratio. Our bioinformatics analysis identified Retinoblastoma 1 (RB1) gene to be a direct target of miR-199a-3p. In RA-FLS, miR-199a-3p directly targetted the 3′-UTR of RB1 mRNA and suppressed endogenous RB1 expression, whereas miR-199a-3p-resistant variant of RB1 was not affected. Silencing RB1 decreased cell proliferation and promoted apoptosis in RA-FLS, an effect comparable with miR-199a-3p overexpression. Enforced expression of RB1 partially restored cell proliferation and attenuated apoptosis in miR-199a-3p-overexpressing RA-FLSs. Conclusion In summary, miR-199a-3p is down-regulated in RA-FLS, and miR-199a-3p inhibits proliferation and induces apoptosis in RA-FLS, partially via targetting RB1. The miR-199a-3p/RB1 pathway may represent a new therapeutic target for RA.

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Section: Discussionmentioning

confidence: 99%

MiR-199a-3p inhibits proliferation and induces apoptosis in rheumatoid arthritis fibroblast-like synoviocytes via suppressing retinoblastoma 1

Wangyang

Wang

et al. 2018

Bioscience Reports

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Contrasting roles of plasminogen deficiency in different rheumatoid arthritis models

Guo

Holmdahl

et al. 2005

Arthritis & Rheumatism

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Objective. To investigate the contrasting roles of plasminogen deficiency between models of collageninduced arthritis (CIA) and antigen-induced arthritis (AIA).Methods. We developed a new animal model of arthritis, which we have called local injection-induced arthritis (LIA). In this model, we replaced methylated bovine serum albumin, which is normally used as an immunogen and is injected intraarticularly into the knee joint, with type II collagen (CII) to induce AIA. The severity of CIA, LIA, and AIA in wild-type and plasminogen-deficient mice was evaluated by clinical scoring or histologic grading. Necrosis was determined by histology and immunohistochemistry.Results. After CII immunization alone, wild-type mice developed arthritis in most of the paws as well as in the knee joints, whereas plasminogen-deficient mice were totally resistant to the disease. Local knee injections of CII or saline slightly enhanced the severity of the knee arthritis in wild-type mice during a 60-day experimental period. Unexpectedly, the plasminogendeficient mice also developed arthritis in joints that were injected with CII or saline. However, the arthritis was milder than that in their wild-type littermates. Sustained tissue necrosis was found only in the plasminogen-deficient mice after the local injection.Conclusion. Our data show that both the antigen and the joint trauma caused by the local injection are critical to explaining the contrasting roles of plasminogen deficiency in CIA and AIA. This further indicates that CIA and AIA have distinct pathogenic mechanisms. The data also suggest that plasmin may be required for the induction of these arthritis models that are critically dependent on complement activation.

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Protective effect of RC-3095, an antagonist of the gastrin-releasing peptide receptor, in experimental arthritis

Oliveira¹,

Grespan²,

Pinto³

et al. 2011

Arthritis & Rheumatism

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Objective. To evaluate the antiinflammatory effects of RC-3095 in 2 experimental models of arthritis, collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA), and to determine the mechanisms of action involved.Methods. RC-3095 was administered daily to mice with CIA and mice with AIA, after induction of disease with methylated bovine serum albumin. Disease incidence and severity were assessed using a clinical index and evaluation of histologic features, respectively. In mice with CIA, gastrin-releasing peptide receptor (GRPR) was detected by immunohistochemical analysis, while in mice with AIA, migration of neutrophils, presence of glycosaminoglycans, and lymphocyte proliferation, determined using the MTT assay, were assessed. Expression of cytokines interleukin-17 (IL-17), IL-1␤, and tumor necrosis factor ␣ (TNF␣) was evaluated in all mouse knees using enzyme-linked immunosorbent assay. Treg cell production was assessed by flow cytometry in the joints of mice with AIA.Results. In mice with AIA, administration of RC-3095 reduced neutrophil migration, mechanical hypernociception, and proteoglycan loss. These findings were associated with inhibition of the levels of all 3 proinflammatory cytokines, decreased lymphocyte proliferation, and increased Treg cell numbers. In the CIA model, treatment with RC-3095 led to a significant reduction in arthritis clinical scores and the severity of disease determined histologically. Synovial inflammation, synovial hyperplasia, pannus formation, and extensive erosive changes were all dramatically reduced in the arthritic mice treated with RC-3095. Furthermore, arthritic mice treated with RC-3095 showed a significant reduction in the concentrations of IL-17, IL-1␤, and TNF␣, and showed a diminished expression of GRPR.Conclusion. These findings suggest that the GRP pathway has a significant role in chronic arthritis, and its inhibition can be explored as a possible therapeutic strategy in rheumatoid arthritis.

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Cited by 11 publications

References 65 publications

MiR-199a-3p inhibits proliferation and induces apoptosis in rheumatoid arthritis fibroblast-like synoviocytes via suppressing retinoblastoma 1

MiR-199a-3p inhibits proliferation and induces apoptosis in rheumatoid arthritis fibroblast-like synoviocytes via suppressing retinoblastoma 1

Contrasting roles of plasminogen deficiency in different rheumatoid arthritis models

Protective effect of RC-3095, an antagonist of the gastrin-releasing peptide receptor, in experimental arthritis

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