Selective glucocorticoid receptor modulator compound A, in contrast to prednisolone, does not induce leptin or the leptin receptor in human osteoarthritis synovial fibroblasts

Malaise, Olivier; Relić, Biserka; Quesada-Calvo, Florence; Charlier, Émilie; Zeddou, Mustapha; Neuville, Sophie; Gillet, Philippe; Louis, Édouard; Seny, Dominique de; Malaise, Michel

doi:10.1093/rheumatology/keu428

Cited by 16 publications

(24 citation statements)

References 19 publications

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“…And, although it is unclear what the effect of classic GCs is on the progression of osteoarthritis, it has been proven that they cause an increase in leptin and its receptor (Ob-R) (Relic et al, 2009). Recent research, however, demonstrated that CpdA, in contrast to glucocorticoids, does not cause an increase in the expression of leptin or its receptor, thereby potentially indicating an improved risk:benefit ratio (Malaise et al, 2014).…”

Section: Side Effectsmentioning

confidence: 99%

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

Sundahl

Bridelance

Libert

et al. 2015

Pharmacology & Therapeutics

174

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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Section: Side Effectsmentioning

confidence: 99%

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

Sundahl

Bridelance

Libert

et al. 2015

Pharmacology & Therapeutics

174

171

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“…If leflunomide is initiated, the patients need to be followed closely for potential secondary loss of efficacy. 4 Nippon Medical School, Tokyo; 5 Kagoshima University, Kagoshima; 6 Juntendo University, Tokyo; 7 Wakayama Medical University, Wakayama; 8 Matsuno Clinic for Rheumatic Diseases, Toyama; 9 Hakkeikai Inc Medical Institution, Shizuoka; 10 The University of Tokyo; 11 Pfizer Japan Inc, Tokyo, Japan Background: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Efficacy and safety of tofacitinib have been shown in RA patients in global Phase 2, Phase 3 (one study included Japanese patients) and long-term extension (LTE) studies and in two Phase 2 and one LTE study in Japanese patients.…”

Section: Ab0429 Short-term Effects Of Low Dose Glucocorticoids On Bonmentioning

confidence: 99%

AB0429 Short-term effects of low dose glucocorticoids on bone metabolism in early rheumatoid arthritis

Vitiello

Viapiana

Malavolta³

et al. 2017

Abstracts Accepted for Publication

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BackgroundGlucocorticoids (GCs) are frequently used in the treatment of Rheumatoid Arthritis (RA). Studies in humans about the effects on bone turnover markers and modulators are poor, and results are discordant and controverse, probably because conducted with different doses and underlying diseases.ObjectivesTo evaluate changes in serum bone turnover markers and Wnt inhibitors at 7- and 30-days after initiation of low dose GCs treatment of early RA.Methods27 adult patients suffering from early RA were prospectively enrolled. Blood tests including C-Reactive Protein (CRP), amino-terminal propeptide of type 1 procollagen (P1NP, marker of bone formation), carboxy-terminal telopeptide of type 1 collagen (CTX, marker of bone resorption), Sclerostin, and Dickkopf-related protein 1 (DKK1) were detected at baseline and 7 and 30 days after starting low dose of GC (methylprednisolone 4 mg/day).ResultsAt baseline we observed a significant positive correlation between CRP and DKK1 serum levels (r=0,63; p<0,05) and between DKK1 and CTX serum levels (r =0,38; p<0,05). A significant decrease in serum levels of CRP, P1NP, and Sclerostin was observed after 7 and 30 days of GC treatment (p<0,05). About DKK1, it has been detected a not significant tendency to decrease after starting GC. CTX serum levels showed no significant changes.ConclusionsThis study has shown that a low dose GC treatment might have complex and conflicting short-term effects on bone metabolism in early RA (a reduction of bone formation, without increase of bone resorption), different from those observed with higher dose, in other diseases or in healthy subjects. The observed decrease in P1NP and Sclerostin serum levels might mean that also low dose of GC could acutely suppress bone formation and induce loss of function and/or number of osteocytes.Disclosure of InterestNone declared

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“…Leptin levels in OA synovial fluid were also increased compared to their corresponding levels in serum 12 , suggesting that leptin has a local effect on OA cartilage. Therefore, the hypothesis that joint cells could produce leptin emerged, and increasing reports indicate that leptin can effectively be produced by joint cells as observed with OA synovial fibroblasts 13,14 . Importantly, in situ analyses also revealed that leptin expression was strongly upregulated in human knee OA chondrocytes and was associated with the severity of the lesions 15 .…”

Section: Introductionmentioning

confidence: 99%

“…However, little is known about molecular mechanisms allowing leptin expression by chondrocytes. Nevertheless, glucocorticoids like prednisolone in addition to their powerful anti-inflammatory properties have been recently reported to be potent stimulators of leptin and leptin receptor (Ob-R) in OA synovial fibroblasts, favoring TGFb signalling through Smad1/5 phosphorylation 13,14,18 .…”

Section: Introductionmentioning

confidence: 99%

Restriction of spontaneous and prednisolone-induced leptin production to dedifferentiated state in human hip OA chondrocytes: role of Smad1 and β-catenin activation

Charlier

Malaise

Zeddou

et al. 2016

Osteoarthritis and Cartilage

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Selective glucocorticoid receptor modulator compound A, in contrast to prednisolone, does not induce leptin or the leptin receptor in human osteoarthritis synovial fibroblasts

Abstract: CpdA, unlike prednisolone, did not induce leptin or Ob-R in human OA synovial fibroblasts, thereby demonstrating an improved risk:benefit ratio.

Cited by 16 publications

References 19 publications

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

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

AB0429 Short-term effects of low dose glucocorticoids on bone metabolism in early rheumatoid arthritis

Restriction of spontaneous and prednisolone-induced leptin production to dedifferentiated state in human hip OA chondrocytes: role of Smad1 and β-catenin activation

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