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Bone marrow adipose tissue and the control of bone mass (HORWOODU19MED)


Project Description

In the UK over 3 million people have osteoporosis leading to over 300,000 fragility fractures per year: this costs £1.9 billion for hip fractures alone. Low bone mass arises from a number of different causes including diet, ageing, genetic predisposition, autoimmune disorders and diabetes (1, 2). Human cross-sectional studies have established an inverse correlation between bone mass and bone marrow adipose tissue (BMAT) particularly in skeletal ageing and osteoporosis, where high marrow adiposity is closely linked to reduced bone integrity and increased fracture risk (3). Study of different osteoporotic models; induced by ageing, sex hormone deficiency and glucocorticoids, supports these findings (4, 5). BMAT and bone forming osteoblasts arise from the same precursor in the bone marrow, mesenchymal stromal cells (MSCs). Adipokines (i.e. adiponectin, leptin), incretins (GLP1 and GIP), and hormones (i.e. GH and insulin) are involved in the modulation of bone remodelling, marrow adipogenesis, and energy metabolism. Hence, metabolic diseases such as diabetes mellitus greatly affect BMAT, bone strength and fracture risk.

We hypothesise that this relationship relates to fate-switching of MSCs between osteoblastic and adipogenic fates. This project will advance our understanding of how the ageing bone marrow environment selects for the differentiation of MSC into adipocytes at the expense of osteoblasts. We have identified a new receptor involved in this process and will test its role in osteoporosis and diabetes models and in patient cohorts. To do this work we will employ in-vitro assays with clinical samples from the metabolic bone clinic at the Norfolk and Norwich University Hospital as well as in-vivo disease models. As disease prevalence increases with our ageing population, understanding how to alter the balance between bone and BMAT will provide insights to disease mechanisms and importantly, future treatments to ameliorate bone loss.

For more information on the supervisor for this project, please go here: https://people.uea.ac.uk/en/persons/n-horwood
The type of programme: PhD
The start date of the project: OCT 2019
Acceptable first degree in Medicine, Biological Sciences and minimum entry requirements is 2:1.

Funding Notes

This PhD studentship is funded by Norwich Medical School. Funding comprises Home/EU fees, a stipend of £15,009 and £1000 per annum to support research training. Overseas applicants may apply but are required to fund the difference between home/EU and overseas tuition fees (in 2019/20 the difference is £14,373 for lab based projects and £11,073 for non-lab based projects but fees are subject to an annual increase).

References

i) Osteogenesis and aging: lessons from mesenchymal stem cells. Infante A, Rodríguez CI. Stem Cell Res Ther. 2018, 9(1):244
ii) Macrophage Polarization and Bone Formation: A review. Horwood NJ. Clin Rev Allergy Immunol. 2016, 51(1):79-86.
iii) The bone-fat interface: basic and clinical implications of marrow adiposity. Devlin MJ, Rosen CJ. Lancet Diabetes Endocrinol. 2015, 3(2):141-7.
iv) Strain dependent differences in glucocorticoid-induced bone loss between C57BL/6J and CD-1 mice. Ersek A, Santo AI, Vattakuzhi Y, George S, Clark AR, Horwood NJ. Sci Rep. 2016, 6:36513.
v) Fully reduced HMGB1 accelerates the regeneration of multiple tissues by transitioning stem cells to GAlert. Lee G, Espirito Santo AI, Zwingenberger S, Cai L, Vogl T, Feldmann M, Horwood NJ, Chan JK, Nanchahal J. PNAS. 2018, 115(19):E4463-E4472.

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