Exploring Glucocorticoid Metabolism as a Therapeutic Target for Bone Wasting Related to Chronic Kidney Disease


   Institute of Clinical Sciences

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  Dr R Hardy, Dr Marie Jones  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Chronic kidney disease (CKD) is a common long-term condition, affecting 1 in 7 people above the age of 65 years in England. This patient population has two- to five-fold increased risk of bone fractures.(1) Bone strength is lower in CKD because associated hormone and electrolyte imbalances impair bone mass and architecture. Secondary hyperparathyroidism is a central factor in this pathology, driving accelerated bone turnover through osteoclast and osteoblast activation. The unique characteristics of CKD-related bone disease preclude the use of conventional bone-protective therapies used for osteoporosis.(1) Hence, this high-risk patient group for bone fractures is underserved with treatments to reduce bone fragility.

Glucocorticoid signalling is elevated in CKD with a prolonged half-life for active glucocorticoids (2). Yet, very little is known about potential interactions between glucocorticoid signalling and other mediators of CKD-related bone disease, or the role of glucocorticoid metabolism in bone in CKD. Through extensive studies in human tissues, primary bone cell cultures and mouse models, we have shown that the glucocorticoid activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11βHSD1) is an important regulator of bone remodelling (3). By modulating glucocorticoid signalling locally within osteoblasts and osteocytes, 11βHSD1 shapes the inhibitory effects of glucocorticoids on bone formation. This concept is illustrated by mice with genetic deletion of 11βHSD1 exhibiting protection against glucocorticoid-induced osteoporosis (4). We hypothesize that 11βHSD1 activity in bone antagonises bone formation in the context of CKD-related bone disease with high bone turnover rates, and that blocking 11βHSD1 ameliorates the bone phenotype in CKD.

Project Aims:

1) Characterise the expression pattern of 11βHSD1 in skeletal bone in the adenine-diet mouse model of renal impairment

2) Evaluate the effect of 11βHSD1 genetic knock-out on renal bone disease in the adenine-diet mouse model

3) Explore the interaction of glucocorticoid and PTH stimulation on osteoblast cultures and osteoclast cultures

Person Specification

Applicants should have a strong background in biology, molecular biology, cell biology or medical sciences and hold or realistically expect to obtain at least an Upper Second Class Honors Degree in a relevant subject. A master’s degree in research or experience in the techniques outlined within this application, whilst not a necessity, would be advantageous. It will be preferable but not essential to have a commitment to immunology or endocrinology research.

How to apply

Informal enquiries should be directed to Dr Rowan Hardy at [Email Address Removed]

Applications should be directed to Viktorija Ziabliceva ([Email Address Removed]). To apply, please send:

• A detailed CV, including your nationality and country of birth;

• Names and addresses of two referees;

• A covering letter highlighting your research experience/capabilities;

• Copies of your degree certificates with transcripts;

• Evidence of your proficiency in the English language, if applicable.

Person Specification

Applicants should have a strong background in biology, molecular biology, cell biology or medical sciences and hold or realistically expect to obtain at least an Upper Second Class Honors Degree in a relevant subject. A master’s degree in research or experience in the techniques outlined within this application, whilst not a necessity, would be advantageous. It will be preferable but not essential to have a commitment to immunology or endocrinology research.

Biological Sciences (4)

References

1. Pimentel A, Ureña-Torres P, Zillikens MC, Bover J, Cohen-Solal M. Fractures in patients with CKD—diagnosis, treatment, and prevention: a review by members of the European Calcified Tissue Society and the European Renal Association of Nephrology Dialysis and Transplantation. Kidney International. 2017;92(6):1343-55.
2. Stroud A, Zhang J, McCormack A. Diagnosing Cushing's disease in the context of chronic kidney disease: a case report and literature review. Eur. 2019;181(4):K29-K35.
3. Hardy RS, Zhou H, Seibel MJ, Cooper MS. Glucocorticoids and Bone: Consequences of Endogenous and Exogenous Excess and Replacement Therapy. Endocr Rev. 2018;39(5):519-48.
4. Fenton CG, Doig CL, Fareed S, Naylor A, Morrell AP, Addison O, et al. 11β-HSD1 plays a critical role in trabecular bone loss associated with systemic glucocorticoid therapy. Arthritis Res Ther. 2019;21(1):188.
5. Metzger CE, Swallow EA, Stacy AJ, Allen MR. Adenine-induced chronic kidney disease induces a similar skeletal phenotype in male and female C57BL/6 mice with more severe deficits in cortical bone properties of male mice. PLoS One. 2021;16(4):e0250438.

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 About the Project