11β-Hydroxysteroid dehydrogenase type 1 within osteoclasts mediates the bone protective properties of therapeutic corticosteroids in chronic inflammation.
Fenton, Chloe G Crastin, Ana Martin, Claire S Suresh, Saicharan Montagna, Isabella Hussain, Bismah Naylor, Amy J Jones, Simon W Hansen, Morten S Gorvin, Caroline M
Fenton, Chloe G
Crastin, Ana
Martin, Claire S
Suresh, Saicharan
Montagna, Isabella
Hussain, Bismah
Naylor, Amy J
Jones, Simon W
Hansen, Morten S
Gorvin, Caroline M
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Affiliation
University of Birmingham; Odense University; University of Nottingham; The University of Sydney; Sandwell and West Birmingham NHS Trust
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Publication date
2022-06-30
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Abstract
Therapeutic glucocorticoids (GCs) are powerful anti-inflammatory tools in the management of chronic inflammatory diseases such as rheumatoid arthritis (RA). However, their actions on bone in this context are complex. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a mediator of the anti-inflammatory actions of therapeutic glucocorticoids (GCs) in vivo. In this study we delineate the role of 11β-HSD1 in the effects of GC on bone during inflammatory polyarthritis. Its function was assessed in bone biopsies from patients with RA and osteoarthritis, and in primary osteoblasts and osteoclasts. Bone metabolism was assessed in the TNF-tg model of polyarthritis treated with oral GC (corticosterone), in animals with global (TNF-tg11βKO), mesenchymal (including osteoblast) (TNF-tg11βflx/tw2cre) and myeloid (including osteoclast) (TNF-tg11βflx/LysMcre) deletion. Bone parameters were assessed by micro-CT, static histomorphometry and serum metabolism markers. We observed a marked increase in 11β-HSD1 activity in bone in RA relative to osteoarthritis bone, whilst the pro-inflammatory cytokine TNFα upregulated 11β-HSD1 within osteoblasts and osteoclasts. In osteoclasts, 11β-HSD1 mediated the suppression of bone resorption by GCs. Whilst corticosterone prevented the inflammatory loss of trabecular bone in TNF-tg animals, counterparts with global deletion of 11β-HSD1 were resistant to these protective actions, characterised by increased osteoclastic bone resorption. Targeted deletion of 11β-HSD1 within osteoclasts and myeloid derived cells partially reproduced the GC resistant phenotype. These data reveal the critical role of 11β-HSD1 within bone and osteoclasts in mediating the suppression of inflammatory bone loss in response to therapeutic GCs in chronic inflammatory disease.
Citation
Fenton CG, Crastin A, Martin CS, Suresh S, Montagna I, Hussain B, Naylor AJ, Jones SW, Hansen MS, Gorvin CM, Price M, Filer A, Cooper MS, Lavery GG, Raza K, Hardy RS. 11β-Hydroxysteroid Dehydrogenase Type 1 within Osteoclasts Mediates the Bone Protective Properties of Therapeutic Corticosteroids in Chronic Inflammation. Int J Mol Sci. 2022 Jun 30;23(13):7334. doi: 10.3390/ijms23137334.
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Article