title: Targeting 11β-hydroxysteroid dehydrogenases: a novel approach to manipulating local glucocorticoid levels with implications for rheumatic disease.
abstract: Systemic glucocorticoid excess causes osteoporosis, insulin resistance and central obesity. Recently it has been recognized that tissue glucocorticoid levels can increase independently of circulating levels. This occurs through increased activity of the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme which is expressed in bone, synovium, liver and adipose tissue. Mice with global 11β-HSD1 deletion exhibit increased severity of experimental arthritis. However, selective disruption of glucocorticoid signalling in osteoblasts and osteocytes attenuates murine experimental arthritis. In addition, such mice are protected against the adverse metabolic features caused by glucocorticoid excess. Taken together, these results indicate that bone cells, through local glucocorticoid signalling, are involved in the regulation of joint inflammation as well as systemic fuel metabolism. Clinical studies have demonstrated that specific inhibitors of 11β-HSD1 improve insulin sensitivity and reduce weight, suggesting that inhibition of this glucocorticoid-activating enzyme may have applications for treating the adverse metabolic features associated with rheumatic disease.
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, UK.
authors.forename: Rowan S
authors.initials: RS
authors.lastname: Hardy
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Seibel
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cooper
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D024821:Metabolic Syndrome / Q000378:metabolism; D010024:Osteoporosis / Q000378:metabolism; D012216:Rheumatic Diseases / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D042842:11-beta-Hydroxysteroid Dehydrogenases