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Regulating Shedding of Syndecan-3: A Novel Approach to Combat Bone Ageing


Project Description

Ageing is associated with bone loss, osteoporosis and fragility fractures, which impact on health and quality of life. However, the molecular mechanisms underlying age-related bone loss are currently largely unknown. We have recently found that syndecan-3 (Sdc3) knockout mice show signs of accelerated bone ageing (unpublished data) characterised by bone loss and a significant reduction in bone strength. Furthermore, in vitro experiments have shown reduced osteoblastic bone formation and mineralisation. However, the mechanism underlying the bone phenotype of the Sdc-3 KO mouse is currently unknown.

Sdc-3, one of four members of the syndecan gene family, is a transmembrane heparan sulphate proteoglycan receptor. It can bind to a wide variety of proteins and is believed to play a role in the signalling of several cytokines such as fibroblast growth factors, Notch and pleiothrophin. Research has shown that all members of the syndecan family are subject to ectodomain shedding, which is the process whereby the extracellular domains of transmembrane proteins are released from the cell surface by proteolytic cleavage of the core protein. Ectodomain shedding is tightly regulated and requires the direct action of proteases referred to as sheddases. This process releases not only the extra-cellular domain of the syndecans, but also any cytokines and growth factors bound to the heparan sulphate chains of the syndecan. Shedding of syndecans has been shown to have effects on the differentiation and activities of a wide variety of cells. We hypothesize that shedding of Sdc3 is an important mediator of osteoblastic bone formation, and regulates the anabolic response to mechanical loading.

The objectives of this studentship are to determine expression and shedding of Sdc3 from osteoblastsand to identify the sheddase(s) responsible. In addition you will determine the effects of inhibition of Sdc3 shedding on osteoblast differentiation and activity and determine the effects of exogenous Sdc3 ectodomain on the anabolic response to mechanical loading in osteoblasts from Sdc3 KO mice. The project will involve a wide range of techniques such as cell culture, qPCR, transfection, western blotting and microscopy and image analysis. The successful candidate will be based within the Department of Musculoskeletal Biology at the Institute of Ageing and Chronic Disease (IACD), University of Liverpool. The IACD aims to perform cutting-edge basic and translational research, with the aim of identifying novel targets for preventing age-related loss of tissue homeostasis. The IACD has state-of-the-art facilities for all the techniques required for this project, including high resolution ex vivo and in vivo µCT.

The student will be supervised by three supervisors, each having distinct expertise. Prof Rob van ’t Hof provides expertise in bone cell biology, animal models of bone disease, imaging technologies and novel drug development. Dr Kazuhiro Yamamoto is an expert in analysis of shedding and sheddases and Dr Anna Daroszewska will provide expertise in clinical and molecular aspects of bone diseases and pre-clinical disease models.

The Institute of Ageing and Chronic Disease is fully committed to promoting gender equality in all activities. In recruitment we emphasize the supportive nature of the working environment and the flexible family support that the University provides. The Institute holds a silver Athena SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives.

To apply please send your CV and a covering letter to Prof van ‘t Hof with a copy to

Funding Notes

Please note: there is NO FUNDING associated with this studentship. The student will be responsible for providing their own living costs and fees plus research costs of £14,000 a year. Information about the costs of postgraduate study can be found at View Website

References

1. F Brito, A Pisconti, G Charlesworth, A Prior , G Bou-Gharios, R van ‘t Hof , A Daroszewska. Novel role of Syndecan-3 (Sdc3) in maintaining bone mass. Calcif Tissue Int https://doi.org/10.1007/s00223-018-0418-0, P049, 2018.

2. K Yamamoto, S Santamaria, K A Botkjaer, J Dudhia, L Troeberg, Y Itoh, G Murphy, H Nagase. Inhibition of Shedding of Low‐Density Lipoprotein Receptor–Related Protein 1 Reverses Cartilage Matrix Degradation in Osteoarthritis. Arthritis Rheumatol. 69: 1246–1256, 2017.

How good is research at University of Liverpool in Clinical Medicine?
(joint submission with Liverpool School of Tropical Medicine)

FTE Category A staff submitted: 143.50

Research output data provided by the Research Excellence Framework (REF)

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