Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists

Stahn, Cindy; Löwenberg, Mark; Hommes, Daniël W.; Buttgereit, Frank

doi:10.1016/j.mce.2007.05.019

Cited by 342 publications

(287 citation statements)

References 45 publications

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“…Another limitation is that the overall interrelationships of prednisone and disease activity on BMI are net effects. We cannot distinguish between individual hypothetical effects explaining weight gain, such as GCinduced increase of appetite or metabolic effects, via the genomic mechanism of transactivation (17,18), and diminished cytokine-induced weight loss. On the other hand, decreasing disease activity might result in increased physical mobility, which could reduce body weight through fat loss.…”

Section: Discussionmentioning

confidence: 99%

Increase of body mass index in a tight controlled methotrexate‐based strategy with prednisone in early rheumatoid arthritis: Side effect of the prednisone or better control of disease activity?

Jurgens

Jacobs

Geenen

et al. 2012

Arthritis Care & Research

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Objective. To clarify whether increase of body weight in patients with early rheumatoid arthritis (RA) upon administration of prednisone is a side effect of prednisone or a result of better control of disease activity, we examined the association of prednisone and disease activity with a subsequent change in body mass index (BMI). Methods. In the Computer Assisted Management in Early Rheumatoid Arthritis Trial-II, patients ages >18 years with early RA (disease duration <1 year and no prior use of disease-modifying antirheumatic drugs) had been randomized to a methotrexate (MTX)-based tight control strategy with either 10 mg of prednisone (MTX ؉ prednisone) or placebo (MTX ؉ placebo). The MTX ؉ prednisone group had lower disease activity, but gained more weight than the MTX ؉ placebo group (mean ؎ SD 2.9 ؎ 4.2 kg versus 1.3 ؎ 5.3 kg; P ‫؍‬ 0.03). Data from patients with monthly measurements of disease activity (Disease Activity Score in 28 joints [DAS28]) and BMI were analyzed with a longitudinal regression (mixed model) analysis with BMI as the dependent variable and treatment strategy and DAS28 as the independent variables, correcting for baseline BMI and possible confounders (sex, age, and rheumatoid factor status). Results. There was no independent association of glucocorticoid therapy with a change in BMI, but a lower DAS28 was associated with an increased BMI 6 months later. The association of the DAS28 with BMI was most strongly present in postmenopausal women. Clinical cutoff points showed a clear association between DAS28 level and the change in BMI 6 months later. Conclusion. Weight gain during treatment with prednisone seems attributable to a reduction of disease activity and is probably, at least partly, regained weight.

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Section: Discussionmentioning

confidence: 99%

Increase of body mass index in a tight controlled methotrexate‐based strategy with prednisone in early rheumatoid arthritis: Side effect of the prednisone or better control of disease activity?

Jurgens

Jacobs

Geenen

et al. 2012

Arthritis Care & Research

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“…Cortisol is one appealing candidate, as evidence suggests that circulating cortisol accesses gametes and the gestating fetus (Graves and Eiler, 1979;Stratholt et al, 1997;Gitau et al, 1998). Furthermore, cortisol, as a part of the glucocorticoid receptor (GR) complex, affects gene transcription and could, ultimately, permanently alter the offspring epigenome (Stahn et al, 2007). Intriguingly, recent evidence also suggests that microRNA, which could itself be regulated by cortisol and has been shown to be regulated by stress, may have a role in intergenerational inheritance (Cortez et al, 2011;Daxinger and Whitelaw, 2012;Honda et al, 2013;Issler and Chen, 2015).…”

Section: Biological Correlates In Offspringmentioning

confidence: 99%

Intergenerational Transmission of Stress in Humans

Bowers

Yehuda

2015

Neuropsychopharmacol

409

269

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The hypothesis that offspring are affected by parental trauma or stress exposure, first noted anecdotally, is now supported empirically by data from Holocaust survivor offspring cohorts and other populations. These findings have been extended to less extreme forms of stress, where differential physical, behavioral, and cognitive outcomes are observed in affected offspring. Parental stress-mediated effects in offspring could be explained by genetics or social learning theory. Alternatively, biological variations stemming from stress exposure in parents could more directly have an impact on offspring, a concept we refer to here as 'intergenerational transmission', via changes to gametes and the gestational uterine environment. We further extend this definition to include the transmission of stress to offspring via early postnatal care, as animal studies demonstrate the importance of early maternal care of pups in affecting offsprings' long-term behavioral changes. Here, we review clinical observations in offspring, noting that offspring of stress-or trauma-exposed parents may be at greater risk for physical, behavioral, and cognitive problems, as well as psychopathology. Furthermore, we review findings concerning offspring biological correlates of parental stress, in particular, offspring neuroendocrine, epigenetic, and neuroanatomical changes, in an attempt to determine the extent of parental stress effects. Although understanding the etiology of effects in offspring is currently impeded by methodological constraints, and limitations in our knowledge, we summarize current information and conclude by presenting hypotheses that have been prompted by recent studies in the field.

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“…After a poorly understood step called activation, the receptor-steroid complex binds as a dimer with high affinity to biologically active DNA sequences [called hormone response elements (HREs)] to recruit additional transcriptional cofactors and modify the rates of transcription of nearby genes by the RNA polymerase complex. Glucocorticoids are an important class of steroids because they affect almost every cell and tissue in the body and are used to treat a variety of conditions, including asthma, autoimmune diseases, and cancer (1). In most experiments, the observed dose-response curves closely match a first-order Hill function.…”

mentioning

confidence: 98%

A theoretical framework for gene induction and experimental comparisons

Ong

Blackford

Kagan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

113

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Ligand-mediated gene induction by steroid receptors is a multistep process characterized by a dose-response curve for gene product that follows a first-order Hill equation. This behavior has classically been explained by steroid binding to receptor being the rate-limiting step. However, this predicts a constant potency of gene induction (EC 50 ) for a given receptor-steroid complex, which is challenged by the findings that various cofactors/reagents can alter this parameter in a gene-specific manner. These properties put strong constraints on the mechanisms of gene induction and raise two questions: How can a first-order Hill dose-response curve (FHDC) arise from a multistep reaction sequence, and how do cofactors modify potency? Here we introduce a theoretical framework in which a sequence of steps yields an FHDC for the final product as a function of the initial agonist concentration. An exact determination of all constants is not required to describe the final FHDC. The theory predicts mechanisms for cofactor/reagent effects on gene-induction potency and maximal activity and it assigns a relative order to cofactors in the sequence of steps. The theory is supported by several observations from glucocorticoid receptor-mediated gene induction. It identifies the mechanism and matches the measured dose-response curves for different concentrations of the combination of cofactor Ubc9 and receptor. It also predicts that an FHDC cannot involve the DNA binding of preformed receptor dimers, which is validated experimentally. The theory is general and can be applied to any biochemical reaction that shows an FHDC.dose-response | Michaelis-Menten | gene expression | steroid receptors | glucocorticoids | pharmacology I n ligand-mediated gene induction, the amount of gene expressed depends on the amount of ligand present. Thus, the specific shape and properties of the dose-response curve of gene induction, which is of crucial importance for development, differentiation, and homeostasis in many biological systems, provide a quantitative means for probing the gene-induction process. In many cases, the dose-response curve in gene induction obeys a sigmoidal curve, but not all sigmoidal curves have the same shape. For example, a dose-response curve obeying a first-order Hill equation or function (Hill coefficient equal to 1) goes from 10 to 90% of maximum activity over an 81-fold change in ligand concentration, whereas only a 9-fold change is required in a secondorder Hill function, which thus has a different shape (Fig. S1). (A first-order Hill function is sometimes called a Michaelis-Menten function.) Depending upon the shape of the dose-response curve, the responsiveness of gene induction to the same variation in ligand concentration will differ greatly. In addition to the shape, the position or potency [i.e., concentration required for 50% of maximal response (EC 50 )] and maximum activity (A max ) of the dose-response curve are required to specify the amount of gene expressed for a given amount of ligand. Despite the vital...

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Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists

Cited by 342 publications

References 45 publications

Increase of body mass index in a tight controlled methotrexate‐based strategy with prednisone in early rheumatoid arthritis: Side effect of the prednisone or better control of disease activity?

Increase of body mass index in a tight controlled methotrexate‐based strategy with prednisone in early rheumatoid arthritis: Side effect of the prednisone or better control of disease activity?

Intergenerational Transmission of Stress in Humans

A theoretical framework for gene induction and experimental comparisons

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