11β-Hydroxysteroid Dehydrogenase Enzymes Modulate Effects of Glucocorticoids in Rheumatoid Arthritis Synovial Cells

Schmidt, Martin; Straub, Rainer H.

doi:10.1159/000362725

Cited by 7 publications

(3 citation statements)

References 36 publications

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“…Such a system has many advantages because the active hormone is produced upon local demand. A similar phenomenon can be observed with glucocorticoids that can be activated or inactivated by 11β-hydroxysteroid dehydrogenases type 1/2 depending on local requirements 40 . It can also be observed with androgens and estrogens in synovial tissue, which depends on local TNF 41 .…”

Section: Discussionsupporting

confidence: 57%

A thyroid hormone network exists in synovial fibroblasts of rheumatoid arthritis and osteoarthritis patients

Pörings

Lowin

Dufner

et al. 2019

Sci Rep

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While patients with rheumatoid arthritis (RA) sometimes demonstrate thyroidal illness, the role of thyroid hormones in inflamed synovial tissue is unknown. This is relevant because thyroid hormones stimulate immunity, and local cells can regulate thyroid hormone levels by deiodinases (DIO). The study followed the hypothesis that elements of a thyroid hormone network exist in synovial tissue. In 12 patients with RA and 32 with osteoarthritis (OA), we used serum, synovial fluid, synovial tissue, and synovial fibroblasts (SF) in order to characterize the local thyroid hormone network using ELISAs, immunohistochemistry, imaging methods, tissue superfusion studies, cell-based ELISAs, flow cytometry, and whole genome expression profiling. Serum/synovial fluid thyroid hormone levels were similar in RA and OA (inclusion criteria: no thyroidal illness). The degradation product termed reverse triiodothyronine (reverse T3) was much lower in serum compared to synovial fluid indicating biodegradation of thyroid hormones in the synovial environment. Superfusion experiments with synovial tissue also demonstrated biodegradation, particularly in RA. Cellular membrane transporters of thyroid hormones, DIOs, and thyroid hormone receptors were present in tissue and SF. Density of cells positive for degrading DIOs were higher in RA than OA. TNF increased protein expression of degrading DIOs in RASF and OASF. Gene expression studies of RASF revealed insignificant gene regulation by bioactive T3. RA and OA synovial tissue/SF show a local thyroid hormone network. Thyroid hormones undergo strong biodegradation in synovium. While bioactive T3 does not influence SF gene expression, SF seem to have a relay function for thyroid hormones.

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Section: Discussionsupporting

confidence: 57%

A thyroid hormone network exists in synovial fibroblasts of rheumatoid arthritis and osteoarthritis patients

Pörings

Lowin

Dufner

et al. 2019

Sci Rep

Self Cite

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“…The tissue availability of active glucocorticoids is dependent on their rate of synthesis from cholesterol, downstream metabolism, excretion and interconversion (28). The latter is mediated by 11β-HSDs.…”

Section: Discussionmentioning

confidence: 99%

Corticosterone suppresses IL-1β-induced mPGE2 expression through regulation of the 11β-HSD1 bioactivity of synovial fibroblasts in vitro

Wei

Zhu

Xiang

et al. 2017

Experimental and Therapeutic Medicine

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The aim of the present study was to investigate the correlation between glucocorticoid activity regulation, prostaglandin E2 (PGE2) synthesis, and synovial inflammation inhibition activity, through microsomal prostaglandin E synthase-1 (mPGES-1) expression regulated by the glucocorticoid pre-receptor regulator, 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1). In the present study, fibroblast-like synovial cells of rats were studied as a cell model. Cells were stimulated with 10 ng/ml interleukin (IL)-1β for 24 h, and were subsequently, within the next 24 h, treated with or without 10−6 mmol/l corticosterone alone or with 100 nmol/l PF915275. At the end of the second 24 h, PGE2 levels in culture supernatants were assayed. Cells were harvested for mRNA evaluation of 11β-HSD1, mPGES-1, IL-1β and tumor necrosis factor (TNF)-α, and protein detection of 11β-HSD1 and mPGES-1 using reverse transcription-qualitative polymerase chain reaction and western blot analysis, respectively. Corticosterone was demonstrated to suppress the mRNA expression levels of inflammatory factors, such as TNF-α and PGE2, induced by IL-1β in vitro. Simultaneously, expression levels of 11β-HSD1 decreased significantly at the mRNA and protein levels (P<0.05). Cortisol concentration in the medium of the group treated with corticosterone was significantly increased (P<0.05) compared with that of the control group; however, the cortisol concentration was decreased in the medium when the conversion bioactivity of 11β-HSD1 was inhibited by PF915275, while the changes in 11β-HSD1 and mPGES-1 mRNA expression levels and PGE2 content were reversed in the medium. These results indicated that a significant positive correlation (P<0.01) may exist between mRNA and protein expression levels. To conclude, 11β-HSD1 is a key regulator for the synthesis of mPGES-1 and PGE2 in the inflammatory synovial cells in vitro, suggesting a potential interference target for osteoarthritis.

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“…In humans, the synovial cell is a major source of inflammatory cytokines such as IL-1, IL-6, and TNFα, all of which play a chief role during the development of RA [7]. Because of these cytokines, NF-κB can be activated and further cause the expression of various inflammatory mediators.…”

Section: Introductionmentioning

confidence: 99%

KPNA2 Contributes to the Inflammatory Processes in Synovial Tissue of Patients with Rheumatoid Arthritis and SW982 Cells

et al. 2015

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Karyopherin-α2 (KPNA2) functions as an adaptor that transports several proteins to the nucleus. We investigated the function and possible mechanisms of KPNA2 involved in rheumatoid arthritis (RA). Western blotting and immunohistochemistry showed the protein expression of KPNA2 increased in synovial tissue of RA patients compared with the healthy controls. Double immunofluorescent staining indicated that KPNA2 co-localized with T cells, macrophage-like synoviocytes, fibroblast-like synoviocytes, and neutrophils in synovial tissue of RA patients. Moreover, the expression of KPNA2 in SW982 cells was increased in a time-dependent manner in response to TNFα stimulation. Both Western blotting and immunofluorescent staining assay revealed the co-localization of KPNA2 and P65 and their translocation from cytoplasma in TNFα-treated SW982 cells. Furthermore, knocking down the expression of KPNA2 by siRNA inhibited TNFα-induced expression of IL-6, MMP-1, and MMP-13 and, more importantly, decreased the P65 phosphorylation in SW982 cells. We therefore suggested that KPNA2 may play a key role in the inflammation process of RA via NF-κB P65 signal transduction pathway.

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11β-Hydroxysteroid Dehydrogenase Enzymes Modulate Effects of Glucocorticoids in Rheumatoid Arthritis Synovial Cells

Cited by 7 publications

References 36 publications

A thyroid hormone network exists in synovial fibroblasts of rheumatoid arthritis and osteoarthritis patients

A thyroid hormone network exists in synovial fibroblasts of rheumatoid arthritis and osteoarthritis patients

Corticosterone suppresses IL-1β-induced mPGE2 expression through regulation of the 11β-HSD1 bioactivity of synovial fibroblasts in vitro

KPNA2 Contributes to the Inflammatory Processes in Synovial Tissue of Patients with Rheumatoid Arthritis and SW982 Cells

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