The rise in expression and activity of 11β-HSD1 in human mesenchymal progenitor cells induces adipogenesis through increased local cortisol synthesis.

11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) plays an important role in pre-receptor glucocorticoid metabolism. This enzyme is expressed in bone, increases with age, and catalyzes the conversion of the inactive glucocorticoid cortisone into the active glucocorticoid cortisol and vice versa. Here we hypothesized that the physiological activity of 11β-HSD1 to produce cortisol in human mesenchymal progenitor cells (hMSC) is principally sufficient to shift the differentiation potential in the direction of adipogenic. We thus investigated differentiating hMSCs and the mesenchymal stem cell line SCP-1 cultured under osteogenic conditions and stimulated with supra-physiological cortisone levels. The release of active cortisol into the medium was monitored and the influence on cell differentiation analyzed. We revealed an increase in 11β-HSD1 expression followed by increased reductive activity of the enzyme, thereby inducing a more adipogenic phenotype of the cell models via cortisol with negative effects on osteogenesis. Through inhibition experiments with the specific inhibitor 10 j, we proved the enzyme specificity for cortisol synthesis and adipogenic differentiation. Increased expression of 11β-HSD1 followed by higher cortisol levels might thus explain bone marrow adiposity followed by reduced bone quality and stability in old age or in situations of supra-physiological glucocorticoid exposure. Copyright © 2021 Elsevier Ltd. All rights reserved.

Citation

Martina Blaschke, Regine Koepp, Frank Streit, Johannes Beismann, Georg Manthey, Mark-Tilmann Seitz, Angelique Kragl, Heide Siggelkow. The rise in expression and activity of 11β-HSD1 in human mesenchymal progenitor cells induces adipogenesis through increased local cortisol synthesis. The Journal of steroid biochemistry and molecular biology. 2021 Jun;210:105850

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PMID: 33639236

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