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Fenton, C.G., Doig, C.L. 
ORCID: 0000-0001-9694-4230, Fareed, S., Naylor, A., Morrell, A.P., Addison, O., Wehmeyer, C., Buckley, C.D., Cooper, M.S., Lavery, G.G., Raza, K. and Hardy, R.S.,
2019.
11β-HSD1 plays a critical role in trabecular bone loss associated with systemic glucocorticoid therapy.
Arthritis Research and Therapy, 21: 188.
ISSN 1478-6362
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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.
| Item Type: | Journal article | ||||||
|---|---|---|---|---|---|---|---|
| Publication Title: | Arthritis Research and Therapy | ||||||
| Creators: | 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. and Hardy, R.S. | ||||||
| Publisher: | Springer | ||||||
| Date: | 2019 | ||||||
| Volume: | 21 | ||||||
| ISSN: | 1478-6362 | ||||||
| Identifiers: |
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| Rights: | 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. | ||||||
| Divisions: | Schools > School of Science and Technology | ||||||
| Record created by: | Jonathan Gallacher | ||||||
| Date Added: | 11 Nov 2019 09:06 | ||||||
| Last Modified: | 17 Dec 2019 14:50 | ||||||
| URI: | https://irep.ntu.ac.uk/id/eprint/38192 |
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