11β-HSD1 plays a critical role in trabecular bone loss associated with systemic glucocorticoid therapy

Abstract

Background: Despite their efficacy in the treatment of chronic inflammation, the prolonged application of therapeutic glucocorticoids (GCs) is limited by significant systemic side effects including glucocorticoid-induced osteoporosis (GIOP). 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a bi-directional enzyme that primarily activates GCs in vivo, regulating tissue-specific exposure to active GC. We aimed to determine the contribution of 11β-HSD1 to GIOP. Methods: Wild type (WT) and 11β-HSD1 knockout (KO) mice were treated with corticosterone (100 μg/ml, 0.66% ethanol) or vehicle (0.66% ethanol) in drinking water over 4 weeks (six animals per group). Bone parameters were assessed by micro-CT, sub-micron absorption tomography and serum markers of bone metabolism. Osteoblast and osteoclast gene expression was assessed by quantitative RT-PCR. Results: Wild type mice receiving corticosterone developed marked trabecular bone loss with reduced bone volume to tissue volume (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N). Histomorphometric analysis revealed a dramatic reduction in osteoblast numbers. This was matched by a significant reduction in the serum marker of osteoblast bone formation P1NP and gene expression of the osteoblast markers Alp and Bglap. In contrast, 11β-HSD1 KO mice receiving corticosterone demonstrated almost complete protection from trabecular bone loss, with partial protection from the decrease in osteoblast numbers and markers of bone formation relative to WT counterparts receiving corticosterone. Conclusions: This study demonstrates that 11β-HSD1 plays a critical role in GIOP, mediating GC suppression of anabolic bone formation and reduced bone volume secondary to a decrease in osteoblast numbers. This raises the intriguing possibility that therapeutic inhibitors of 11β-HSD1 may be effective in preventing GIOP in patients receiving therapeutic steroids.

Publication DOI: https://doi.org/10.1186/s13075-019-1972-1
Divisions: College of Engineering & Physical Sciences > School of Infrastructure and Sustainable Engineering > Chemical Engineering & Applied Chemistry
Additional Information: © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Funding: Diamond Light Source (proposal MT16654-1) on beamline I13-2 with beamtime awarded through the Diamond Birmingham Collaboration. This research was supported by the Arthritis Research UK grants (Reference: 19859 & 20843) and Wellcome Trust Senior Fellowship (GGL-104612/Z/14/Z).
Full Text Link:
Related URLs: https://arthrit ... 3075-019-1972-1 (Publisher URL)
PURE Output Type: Article
Published Date: 2019-08-16
Accepted Date: 2019-08-07
Authors: Fenton, C. G.
Doig, C. L.
Fareed, S.
Naylor, A.
Morrell, A. P.
Addison, O.
Wehmeyer, C.
Buckley, C. D.
Cooper, M. S.
Lavery, G. G.
Raza, K.
Hardy, R. S.

Download

[img]

Version: Published Version

License: Creative Commons Attribution

| Preview

Export / Share Citation


Statistics

Additional statistics for this record