Differential mechanism of NF‐κB inhibition by two glucocorticoid receptor modulators in rheumatoid arthritis synovial fibroblasts

Gossye, Valerie; Elewaut, Dirk; Bougarne, Nadia; Bracke, Debby; Calenbergh, Serge Van; Haegeman, Guy; Bosscher, Karolien De

doi:10.1002/art.24963

Cited by 57 publications

(44 citation statements)

References 47 publications

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“…5D and F). However, in contrast with previous research in adenocarcinomic human alveolar epithelial cells (A549) and in rheumatoid arthritis synovial fibroblasts (FLS) [37,42], CpdA is unexpectedly unable to significantly repress gene expression levels of MCP-1, IL1b and TNFa (Fig. 5B, C and E), indicating cell-specific mechanisms.…”

Section: Both Dex and Cpda Diminish Pro-inflammatory Gene Expression contrasting

confidence: 69%

Glucocorticoids and the non-steroidal selective glucocorticoid receptor modulator, compound A, differentially affect colon cancer-derived myofibroblasts

Drebert

Bracke

Beck

2015

The Journal of Steroid Biochemistry and Molecular Biology

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Section: Both Dex and Cpda Diminish Pro-inflammatory Gene Expression contrasting

confidence: 69%

Glucocorticoids and the non-steroidal selective glucocorticoid receptor modulator, compound A, differentially affect colon cancer-derived myofibroblasts

Drebert

Bracke

Beck

2015

The Journal of Steroid Biochemistry and Molecular Biology

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“…For the SEGRM CpdA it has been reported that CpdA blocks all mitogen-activated protein kinases (MAPKs) in human rheumatoid arthritis fibroblast-like synoviocytes, albeit in a GRindependent manner (Gossye et al, 2009). Furthermore, CpdA enhances the phosphorylation of c-Jun N-terminal kinase JNK and thus its kinase activity in L929sA cells, also in a GR-independent manner.…”

Section: Non-genomic Pathwaymentioning

confidence: 98%

Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds

Sundahl

Bridelance

Libert

et al. 2015

Pharmacology & Therapeutics

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186

171

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Glucocorticoids remain the frontline treatment for inflammatory disorders, yet represent a double-edged sword with beneficial therapeutic actions alongside adverse effects, mainly in metabolic regulation. Considerable efforts were made to improve this balance by attempting to amplify therapeutic beneficial anti-inflammatory actions and to minimize adverse metabolic actions. Most attention has focused on the development of novel compounds favoring the transrepressing actions of the glucocorticoid receptor, assumed to be important for anti-inflammatory actions, over the transactivating actions, assumed to underpin the undesirable actions. These compounds are classified as selective glucocorticoid receptor agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). The latter class is able to modulate the activity of a GR agonist and/or may not classically bind the glucocorticoid receptor ligand-binding pocket. SEGRAs and SEGRMs are collectively denominated SEGRAMs (selective glucocorticoid receptor agonists and modulators). Although this transrepression vs transactivation concept proved to be too simplistic, the developed SEGRAMs were helpful in elucidating various molecular actions of the glucocorticoid receptor, but have also raised many novel questions. We discuss lessons learned from recent mechanistic studies of selective glucocorticoid receptor modulators. This is approached by analyzing recent experimental insights in comparison with knowledge obtained using mutant GR research, thus clarifying the current view on the SEGRAM field. These insights also contribute to our understanding of the processes controlling glucocorticoid-mediated side effects as well as glucocorticoid resistance. Our perspective on non-steroidal SEGRAs and SEGRMs considers remaining opportunities to address research gaps in order to harness the potential for more safe and effective glucocorticoid receptor therapies.

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“…Furthermore in contrast to the classic steroid DEX, CpdA treatment leads to a clear cytoplasmic relocalization of NF-B in RA primary synovial fibroblasts (FLS). A dual pathway, partially dependent and partially independent of GR, was proposed to explain the gene-inhibitory effects of CpdA on NF-B in RA FLS [55]. Recently, the CpdA-mediated decrease of corticosteroidbinding globulin (CBG), adrenocorticotropic hormone (ACTH) and luteinizing hormone (LH) levels in rats has been linked to direct transcriptional regulatory events at the promoters of these genes [54].…”

Section: Non-steroidal Gr Modulatorsmentioning

confidence: 99%

Selective Glucocorticoid Receptor modulators

Bosscher

2010

The Journal of Steroid Biochemistry and Molecular Biology

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112

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Differential mechanism of NF‐κB inhibition by two glucocorticoid receptor modulators in rheumatoid arthritis synovial fibroblasts

Cited by 57 publications

References 47 publications

Glucocorticoids and the non-steroidal selective glucocorticoid receptor modulator, compound A, differentially affect colon cancer-derived myofibroblasts

Glucocorticoids and the non-steroidal selective glucocorticoid receptor modulator, compound A, differentially affect colon cancer-derived myofibroblasts

Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds

Selective Glucocorticoid Receptor modulators

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