ArticleInflammation research : official journal of the European Histamine Research Society ... [et al.]2025
Dexamethasone regulates gene expression in chondrocytes through MKP-1 and downregulates cholesterol hydroxylases CH25H and CYP7B1.
Article in Inflammation research : official journal of the European Histamine Research Society ... [et al.], 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
objectiveMitogen-activated protein kinase phosphatase-1 (MKP-1) is an anti-inflammatory enzyme whose expression is increased by glucocorticoids (GCs). MKP-1 dephosphorylates and thereby inactivates mitogen-activated protein kinases (MAP kinases) which are major signaling pathways mediating proinflammatory effects of various extracellular factors to gene expression. In this study, we examined the regulatory effects of the synthetic glucocorticoid dexamethasone on the expression of a panel of genes previously identified as the top 15 critical mediators in the pathogenesis of osteoarthritis (OA). Furthermore, we investigated the hypothesis that MKP-1 is involved in mediating these glucocorticoid-induced effects in chondrocytes.
methodsThe effects of dexamethasone on the interleukin-1β-induced expression of OA target genes were investigated with RNA-seq and quantitative RT-PCR in primary cultured chondrocytes from wild-type and MKP-1 deficient mice, and from OA patients undergoing joint replacement surgery.
resultsUnder these conditions, dexamethasone was found to significantly alter the expression of seven out of the 15 OA-related genes including two cholesterol hydroxylases, namely cholesterol 25-hydroxylase (CH25H) and 25-hydroxycholesterol 7-hydroxylase (also known as cytochrome P450 family 7 subfamily B member 1, CYP7B1). Dexamethasone attenuated the interleukin-1β -induced expression of CH25H and CYP7B1 in primary chondrocytes of wild-type mice and in primary human OA chondrocytes, but the dexamethasone effect was absent (CYP7B1) or reduced (CH25H) in chondrocytes from MKP-1 deficient mice. Furthermore, the p38 MAP kinase inhibitor BIRB796 significantly inhibited CH25H expression while the JNK MAP kinase inhibitor SP600125 attenuated CYP7B1 expression in human OA chondrocytes.
conclusionsIn conjunction with previous findings, the current data substantiate the role of MKP-1 as a protective factor in chondrocytes and highlight its potential as a therapeutic target for the treatment of osteoarthritis, because increased levels of cholesterol and its metabolism by CH25H and CYP7B1 are involved in the pathogenesis of OA, particularly in its obesity-associated phenotype.
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