Loss of glucocorticoid rhythm induces an osteoporotic phenotype in female mice
Standard
Loss of glucocorticoid rhythm induces an osteoporotic phenotype in female mice. / Schilperoort, Maaike; Kroon, Jan; Kooijman, Sander; Smit, Annelies E; Gentenaar, Max; Mletzko, Kathrin; Schmidt, Felix N; van Ruijven, Leo; Busse, Björn; Pereira, Alberto M; Appelman-Dijkstra, Natasha M; Bravenboer, Nathalie; Rensen, Patrick C N; Meijer, Onno C; Winter, Elizabeth M.
In: AGING CELL, Vol. 20, No. 10, e13474, 10.2021.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Loss of glucocorticoid rhythm induces an osteoporotic phenotype in female mice
AU - Schilperoort, Maaike
AU - Kroon, Jan
AU - Kooijman, Sander
AU - Smit, Annelies E
AU - Gentenaar, Max
AU - Mletzko, Kathrin
AU - Schmidt, Felix N
AU - van Ruijven, Leo
AU - Busse, Björn
AU - Pereira, Alberto M
AU - Appelman-Dijkstra, Natasha M
AU - Bravenboer, Nathalie
AU - Rensen, Patrick C N
AU - Meijer, Onno C
AU - Winter, Elizabeth M
N1 - © 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
PY - 2021/10
Y1 - 2021/10
N2 - Glucocorticoid (GC)-induced osteoporosis is a widespread health problem that is accompanied with increased fracture risk. Detrimental effects of anti-inflammatory GC therapy on bone have been ascribed to the excess in GC exposure, but it is unknown whether there is also a role for disruption of the endogenous GC rhythm that is inherent to GC therapy. To investigate this, we implanted female C57Bl/6J mice with slow-release corticosterone (CORT) pellets to blunt the rhythm in CORT levels without inducing hypercortisolism. Flattening of CORT rhythm reduced cortical and trabecular bone volume and thickness, whilst bone structure was maintained in mice injected with supraphysiologic CORT at the time of their endogenous GC peak. Mechanistically, mice with a flattened CORT rhythm showed disrupted circadian gene expression patterns in bone, along with changes in circulating bone turnover markers indicative of a negative balance in bone remodelling. Indeed, double calcein labelling of bone in vivo revealed a reduced bone formation in mice with a flattened CORT rhythm. Collectively, these perturbations in bone turnover and structure decreased bone strength and stiffness, as determined by mechanical testing. In conclusion, we demonstrate for the first time that flattening of the GC rhythm disrupts the circadian clock in bone and results in an osteoporotic phenotype in mice. Our findings indicate that at least part of the fracture risk associated with GC therapy may be the consequence of a disturbed GC rhythm, rather than excess GC exposure alone, and that a dampened GC rhythm may contribute to the age-related risk of osteoporosis.
AB - Glucocorticoid (GC)-induced osteoporosis is a widespread health problem that is accompanied with increased fracture risk. Detrimental effects of anti-inflammatory GC therapy on bone have been ascribed to the excess in GC exposure, but it is unknown whether there is also a role for disruption of the endogenous GC rhythm that is inherent to GC therapy. To investigate this, we implanted female C57Bl/6J mice with slow-release corticosterone (CORT) pellets to blunt the rhythm in CORT levels without inducing hypercortisolism. Flattening of CORT rhythm reduced cortical and trabecular bone volume and thickness, whilst bone structure was maintained in mice injected with supraphysiologic CORT at the time of their endogenous GC peak. Mechanistically, mice with a flattened CORT rhythm showed disrupted circadian gene expression patterns in bone, along with changes in circulating bone turnover markers indicative of a negative balance in bone remodelling. Indeed, double calcein labelling of bone in vivo revealed a reduced bone formation in mice with a flattened CORT rhythm. Collectively, these perturbations in bone turnover and structure decreased bone strength and stiffness, as determined by mechanical testing. In conclusion, we demonstrate for the first time that flattening of the GC rhythm disrupts the circadian clock in bone and results in an osteoporotic phenotype in mice. Our findings indicate that at least part of the fracture risk associated with GC therapy may be the consequence of a disturbed GC rhythm, rather than excess GC exposure alone, and that a dampened GC rhythm may contribute to the age-related risk of osteoporosis.
U2 - 10.1111/acel.13474
DO - 10.1111/acel.13474
M3 - SCORING: Journal article
C2 - 34592793
VL - 20
JO - AGING CELL
JF - AGING CELL
SN - 1474-9718
IS - 10
M1 - e13474
ER -
