PhD: Mapping organic and inorganic chemistry with ageing in bone tissue

Bone plays vital roles in the body. Structurally, through supporting body movement and protection of internal organs, and chemically, acting as a reservoir of minerals, blood cell production and molecules for endocrine regulation. It is a biological composite of an inorganic phase (predominantly calcium phosphate) and organic phase, the latter is dominated by collagen molecules that are arranged into fibrils and fibres, within gaps of which the nucleation of mineral crystals occurs.
Recent advances in imaging technology, including those by members of this team using synchrotron-based elemental mapping, have started to improve our characterisation of the inorganic component of bone at resolutions not possible using conventional methods. However, these latest signals have yet to be linked with spatially mapping organic phase signals that drive bone growth and remodelling. For example, in addition to collagen, there are thousands of other proteins present, some of which play a role in directing the mineralization and growth of bone. The size, shape, and arrangement of the bone crystals influence the mechanical behaviour of bone, but these are affected by several factors involving bone remodelling and have consequences for crack initiation and propagation. Yet it is known that not only do a wide range of non-collagenous-proteins (NCPs) and other biomolecules influence this growth but age-related changes to collagen, such as advanced glycation end product and cross-linking formation, can also alter growth.
Traditional methods, such as immunohistochemistry, are targeted approaches, whereas advances in proteomic methods now allow for untargeted ways of investigating a much wider range of organic signals. We have begun to study the aging proteomes of bone (Procopio et al. 2017), identifying a suite of proteins that appear to correlate with skeletal aging, some of which clearly have direct functional relationships, e.g., fetuin-A with bone elongations, but there are many more organic signals of the cyclical remodelling process, whether growth factors being released as part of the activation phase, or enzymes as part of the resorption phase. Through the incorporation of imaging mass spectrometry in addition to shotgun proteomics, this project will seek to integrate complementary multiscale datasets that inform the structural properties and both inorganic as well as organic chemistry of bone throughout growth and remodelling by analysing entire cross-sectional rat limb samples. This will aim to promote a step-change in the understanding of how the inorganic and organic components of bone interact to provide bone with its material properties and structure, down to the cellular level in three-dimensions.

http://www.buckley.lab.manchester.ac.uk/
http://www.ical.manchester.ac.uk/
https://www.micra.manchester.ac.uk/