Widespread regulation of gene expression by glucocorticoids in chondrocytes from patients with osteoarthritis as determined by RNA-Seq

Pemmari, Antti; Leppänen, Tiina; Hämäläinen, Mari; Moilanen, Teemu; Vuolteenaho, Katriina; Moilanen, Eeva

doi:10.1186/s13075-020-02289-7

Cited by 27 publications

(13 citation statements)

References 54 publications

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“…Recently, Pemmari and colleagues examined the global gene expression profiles of chondrocytes that were treated with dexamethasone for 24h by RNA-Seq. They found that dexamethasone affected lipid and glucose metabolism-related genes in addition to their anti-inflammatory, anticatabolic, and extracellular matrix-targeting effects [9]. In human, many inflammatory genes are downstream genes of glucocorticoids.…”

Section: Classification Of Glucocorticoidsmentioning

confidence: 99%

Glucocorticoids are double-edged sword in the treatment of COVID-19 and cancers

Yang¹,

Yu²

2021

Int. J. Biol. Sci.

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Glucocorticoids are important steroid hormones. As an outstanding scientific discovery, the scientist who discovered glucocorticoids was awarded the Nobel Prize in Physiology and Medicine in 1950. Cortisone (hydrocortisone) is a natural glucocorticoid, which is secreted with circadian rhythm by the cortical cells of adrenal glands. Physiologically, about 10-20 mg of hydrocortisone are secreted each day for maintaining homeostasis. Since the biological half-life of natural glucocorticoid is short, scientists developed various synthetic glucocorticoids including prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, betamethasone, and so on. These synthetic glucocorticoids are generated by modifying some structures based on the cortisone backbone, leading to extension of their biological half-life with stronger activities. In the face of severe infection, allergy, shock, trauma, pain, and other stresses, the demand for glucocorticoids increases dramatically. It is critical to supplement extra glucocorticoids to protect the biological functions of vital organs. However, the amount and duration of glucocorticoid administration need to be carefully adjusted, because a series of side effects may occur after long-term or high-dose usage of glucocorticoids. This review article will discuss the application of glucocorticoids in the treatment of patients with severe or critical COVID-19 and solid tumors of advanced stage. The controversy of using glucocorticoid in medical community will also be discussed. This review article will help doctors and basic researchers better understand the practical application of glucocorticoids.

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Section: Classification Of Glucocorticoidsmentioning

confidence: 99%

Glucocorticoids are double-edged sword in the treatment of COVID-19 and cancers

Yang¹,

Yu²

2021

Int. J. Biol. Sci.

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“…They exert their effects by suppressing the expression of proinflammatory genes and by enhancing the expression of anti-inflammatory factors, such as MKP-1 [ 21 ]. We have previously shown that the glucocorticoid dexamethasone has widespread effects on gene expression of human OA chondrocytes [ 23 ]. Glucocorticoids are known to enhance the expression of MKP-1 in chondrocytes, macrophages [ 30 , 31 ], airway epithelial and smooth muscle cells [ 32 , 33 ] and endothelial cells [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…We have recently shown that the glucocorticoid dexamethasone has a widespread effect on the gene expression of primary human OA chondrocytes [ 23 ]. We hypothesized that the effects of dexamethasone on gene expression in chondrocytes could be at least partly mediated through MKP-1.…”

Section: Introductionmentioning

confidence: 99%

Dexamethasone Attenuates the Expression of MMP-13 in Chondrocytes through MKP-1

Lehtola

Nummenmaa

Tuure

et al. 2022

IJMS

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Mitogen-activated protein kinase phosphatase-1 (MKP-1) is upregulated in inflammation and reduces the activity of proinflammatory mitogen-activated protein kinases (MAP kinases) by dephosphorylation. MAP kinases are intracellular signaling pathways that mediate the cellular effects of proinflammatory cytokines. In the present study, we investigated the effects of the glucocorticoid dexamethasone on the expression of catabolic enzymes in chondrocytes and tested the hypothesis that these effects are mediated through MKP-1. Dexamethasone was found to significantly attenuate the expression of matrix metalloproteinase (MMP)-13 in human OA chondrocytes as well as in chondrocytes from MKP-1 WT mice, but not in chondrocytes from MKP-1 KO mice. Dexamethasone also increased the expression of MKP-1 in murine and human OA chondrocytes. Furthermore, p38 MAP kinase inhibitors significantly attenuated MMP-13 expression in human OA chondrocytes, while JNK MAP kinase inhibitors had no effect. The results indicate that the effect of dexamethasone on MMP-13 expression in chondrocytes was mediated by an MKP-1 and p38 MAP kinase-dependent manner. These findings, together with previous results, support the concept of MKP-1 as a protective factor in articular chondrocytes in inflammatory conditions and as a potential drug target to treat OA.

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“…At the molecular level, GCs have been mainly described as transcriptional regulators, via binding to the GR and modulating the expression of genes that contain GREs in their promoters (8, 9, 27, 45). There is an increased appreciation of the role of GCs as post-transcriptional modulators, directly via GR as an RBP or via other RBPs such as ZFP36 or ZFP36L2 (12–14, 40, 46). There is also previous evidence that ZFP36L1 and ZFP36L2 mRNA or protein are upregulated in response to dexamethasone in some cell types (40, 47–49), but not bronchial epithelial cells so far.…”

Section: Discussionmentioning

confidence: 99%

The RNA binding proteins ZFP36L1 and ZFP36L2 modulate transcriptional and post-transcriptional genome-wide effects of glucocorticoids

Rynne

Ortiz-Zapater

Khooshemehri

et al. 2022

Preprint

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Glucocorticoids (GCs) are one of the most used anti-inflammatory drugs worldwide. Despite their widespread use, our understanding of their post-transcriptional effects remains poorly understood. The tristetraprolin (TTP) RNA binding protein (RBP) family (ZFP36, ZFP36L1 and ZFP36L2) has been implicated in inflammation regulation via binding to AU-rich elements (ARE) in mRNAs, with TTP being implicated in GC modulation. We hypothesised that ZFP36L1 and ZFP36L2 are part of the GC pathway and tested this hypothesis in bronchial epithelium, which commonly encounters GC in vivo upon inhalation. Our data show that dexamethasone, a commonly used GC, modulated the levels, subcellular localisation and RNA binding of ZFP36L1/L2. Employing Frac-seq (subcellular fractionation and RNA-sequencing), we show that GC modulated distinct subsets of RNAs in a subcellular-dependent manner. In addition to their mostly known transcriptional effects (116 differentially expressed genes, DEGs), GCs modified the binding to monosomes of myriad mRNAs (83 differentially bound genes, DBGs). We also demonstrate that ZFP36L1/L2 modulated gene expression mainly at the total cytoplasmic and polyribosome binding levels. ZFP36L1/L2 down-regulation led to an increase in ARE-containing mRNAs and a pronounced modification of the effects of GC on gene expression. We observed a small overlap of genes modulated by GCs when comparing control and ZFP36L1/L2 knockdown cells, in a subcellular-dependent manner Our data also suggest a novel role for these RBPs and GCs in epithelial biology via regulation of mRNAs encoding proteins important for epithelial cell function including cellular structure. We believe that our data has further implications in how we investigate gene expression. We show the power of employing sub-cellular fractionation when analysing genome-wide effects for known ″transcriptional modulators″ such as GCs, as well as a tool to demonstrate the extent of the effect of RBPs on gene expression modulation beyond total RNA levels.

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Widespread regulation of gene expression by glucocorticoids in chondrocytes from patients with osteoarthritis as determined by RNA-Seq

Cited by 27 publications

References 54 publications

Glucocorticoids are double-edged sword in the treatment of COVID-19 and cancers

Glucocorticoids are double-edged sword in the treatment of COVID-19 and cancers

Dexamethasone Attenuates the Expression of MMP-13 in Chondrocytes through MKP-1

The RNA binding proteins ZFP36L1 and ZFP36L2 modulate transcriptional and post-transcriptional genome-wide effects of glucocorticoids

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