Investigating glucocorticoids as mediators of increased bone marrow adiposity and bone loss
Creators: name: Lovdel, Andrea
Publisher: name: The University of Edinburgh
Year: 2020
Subjects: bone marrow adipose tissue
BMAT
bone
caloric restriction

description: In addition to white and brown adipose tissue (WAT and BAT, respectively), there is a third major adipose depot, called bone marrow adipose tissue (BMAT), the formation and function of which is poorly understood. In healthy adults, BMAT accounts for up to 70% of bone marrow (BM) volume and further increases during various conditions, such as ageing, osteoporosis, obesity, oestrogen deficiency, glucocorticoid (GC) therapy and, most surprisingly, during caloric restriction (CR) in animals and anorexia nervosa (AN) in humans. Furthermore, such BMAT expansion often coincides with bone loss. However, the mechanisms regulating BMAT expansion in these adverse conditions remain incompletely understood. One possibility is that GCs contribute to BMAT expansion and bone loss during CR and ageing. Long-term GC treatment can induce bone loss and BMAT expansion. One recent study found that CR is associated with elevated circulating GCs in mice, but not in rabbits; the mice also have increased BMAT, whereas the rabbits do not. Furthermore, GCs have been reported to increase during starvation or AN in humans, followed by BMAT expansion. Tissue regeneration of GCs is regulated by 11ß-hydroxysteroid dehydrogenase (11ß-HSD1), which generates active cortisol in humans and corticosterone in rodents, from inactive cortisone and 11-dehydrocorticosterone (11-DHC), respectively. Notably, 11ß-HSD1 KO mice resist the Cushingoid effects of GC excess. Thus, the hypothesis for this thesis is that GC excess contributes to BMAT expansion and bone loss during CR and ageing, and that 11ß-HSD1 KO mice would therefore resist these effects. Herein, I addressed this hypothesis by characterising the BMAT and bone phenotypes of control and 11ß-HSD1 KO mice in response to CR and ageing. To investigate the effects on BMAT and bone remodelling during CR, male and female C57BL/6J mice lacking 11ß-HSD1 (KO) or littermate controls (WT) were fed ad libitum (AL) or 70% of AL intake (CR) from 9-15 weeks of age. Whereas, to investigate the effects of ageing on BMAT and bone remodelling, KO and WT mice of both sexes were characterised at 15, 42 and 70 weeks of age. Following CR, all mice had decreased body mass and increased plasma and BM corticosterone concentrations. Cortical bone loss was present with CR in all mice, and CR significantly increased BMAT in WT males and females, and in KO females. However, KO males resisted CR-induced BMAT expansion. Unexpectedly, the KO males also had significantly increased circulatory and BM progesterone, suggesting that this hormone might be a potential candidate. The aged mice exhibited increased circulating corticosterone and BMAT, and decreased bone mass, compared to young mice. However, unlike during CR, KO males did not resist age-related BMAT expansion, suggesting that the mechanisms for this differ to those responsible for BMAT expansion during CR. Correlation data between BMAT, bone parameters and GCs suggest these factors may be linked, but do not inform cause and effect. Although 11ß-HSD1 may play a role in BMAT expansion, the physiological significance remains unknown. These findings suggest that local corticosterone regeneration might mediate BMAT expansion during CR in males only. However, another possibility is that progesterone might influence the blockade of BMAT, since progesterone is the precursor to oestradiol, and oestradiol blocks BMAT formation. Given the sexual dimorphism, in females other mechanisms likely influence BMAT expansion during CR. Bone loss was observed in all mice, suggesting a limited role for 11ß-HSD1 in bone formation. Results in the aged mice suggest that 11ß-HSD1 does not influence BMAT expansion in this context. However, ageing-associated corticosterone and BMAT expansion did demonstrate a correlation with bone loss, while corticosterone was positively associated with BMAT volume in aged females. To conclude, 11ß-HSD1 activity is required for CR-induced BMAT expansion in males, and GC excess might contribute to ageing-associated BMAT expansion in females. Considering the broad physiological and pathological implications of BMAT, it will be important for future studies to further dissect the relationship between GC excess, BMAT expansion and bone loss.