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|Title: ||The Effects of Excessive Endogenous Glucocorticoid Levels on Cartilage and Bone of Postnatal Mice|
|Authors: ||Zhang, Yaqing|
|Issue Date: ||26-Feb-2014|
|Publisher: ||University of Sydney. Sydney Medical School. Concord Clinical School.|
|Abstract: ||Glucocorticoid therapy of paediatric deceases is limited by significant side effects, which in particular concern musculoskeletal metabolism and development. The mechanisms by which excessive glucocorticoid concentrations affect early postnatal cartilage and bone development are poorly understood. Using a mouse line in which the glucocorticoid receptor (GR) was deleted in the hypothalamus and pituitary (Fabp4Cre+;GRfl/fl, also referred to as “GRKO-HTP mice”), I studied the effects of endogenous hypercortisolism on the immediate postnatal skeletal develop¬ment in newborn mice. In the GRKO-HTP mouse line, the central deletion of the GR results in the disruption of normal hypothalamic-pituitary-adrenal (HPA) feedback and thus leads to a progressive rise in serum corticosterone levels after birth.
Early postnatal hypercortisolism interferes with normal growth plate development through inhibition of chondrocyte proliferation and induction of condrocyte apoptosis. These effects are mediated through the suppressive action of gluco¬corticoids on the expression of parathyroid hormone–related protein (PTHrP) and Indian Hedgehog (Ihh) in the growth plate. In bone, glucocorticoids induce a dose-dependent catabolic and/or anabolic response, with the osteoblast rather than the osteoclast being the main target. In addition, postnatal hypercortisolism was associated with abnormal kidney and pulmonary morphology and function in GRKO-HTP mice. Thus, 10-day old GRKO-HTP mice developed severe hypokalaemia which, in combination with progressive pulmon¬ary changes lead to early mortality.
Overall, early postnatal hypercortisolism causes growth retardation due to growth plate failure, whereas the effects on bone appear to be dose-dependent and can be either anabolic or catabolic.|
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|Rights and Permissions: ||The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.|
|Type of Work: ||PhD Doctorate|
|Type of Publication: ||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (University of Sydney Access only)|
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|ZHANG Yaqing - final thesis.pdf||PhD Thesis||4.83 MB||Adobe PDF|
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