SFEBES2023 Oral Communications Bone and Calcium (6 abstracts)
The role of glucocorticoid metabolism in the skeletal pathophysiology of chronic kidney disease
Arjan Shanker 1 , Ben Cassidy 1 , Ana Crastin 1 , Gowsihan Poologasundarampillai 2 , Rowan Hardy 1 , Lorraine Harper 3 , Simon W. Jones 4 & Michael Sagmeister 1
1IMSR, University of Birmingham, Birmingham, United Kingdom. 2Dentistry, University of Birmingham, Birmingham, United Kingdom. 3Applied Health Research, University of Birmingham, Birmingham, United Kingdom. 4IIA, University of Birmingham, Birmingham, United Kingdom
Background: Osteoporosis is a common feature of chronic kidney disease (CKD), associated with premature mortality. Glucocorticoids (GCs) are steroid hormones, that in excess, can drive the suppression of bone formation. We have shown that the glucocorticoid (GC) activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is dysregulated in CKD, where it may contribute to the suppression of bone formation. We utilised a murine model of CKD with transgenic deletion of 11β-HSD1 to examine its contribution to bone metabolism.
Methods: 8-week-old male mice with wild-type (WT) or 11β-HSD1 knockout (11BKO) genetic background received either normal chow diet or chow treated with 0.15% adenine for 7-weeks to induce renal impairment. Renal function was determined by histology and serum urea and creatinine (IDEXX). Within tibia, trabecular bone parameters were assessed by micro-CT and measures of anabolic and catabolic bone metabolism assessed by quantitative RT-PCR.
Results: In both WT and 11BKO animals, adenine induced comparable renal impairment with increased urea and creatinine levels in both WT (fold increase 3.16 and 2.79, P<0.0001) and 11BKO mice (fold increase 4.69 and 4.10, P<0.0001 respectively) with increased atrophy of glomeruli. In both groups, renal impairment coincided with a marked reduction in bone volume/total tissue volume (BV/TV), trabecular number (TrbN) and thickness (TrbTh). Bone loss was more marked in 11β-HSD1 animals relative to WT controls (BV/TV; WT 48% vs 11BKO 73%; P<0.001) with greater loss in TrbN and TrbTh. However, no changes in markers of formation or resorption were apparent between groups at this timepoint.
Conclusion: This study reveals that the adenine model of CKD results in marked systemic bone loss that matches that seen with human disease. Blockade of steroid metabolism in 11BKO animals exacerbated this phenotype in vivo. The mechanism underpinning observation has yet to be determined.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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