Characterisation of the intimate relationship between collagen and mineral during skeletal biomineralisation.

Lead Research Organisation: University of Edinburgh
Department Name: The Roslin Institute

Abstract

The development and growth of the skeleton depends on the integration of events directing cells derived from the primitive mesenchyme to produce cartilage and bone matrix, and to mineralise and remodel that matrix. Bone is a composite material made up of mostly collagen and mineral whose combined material properties make bone strong and tough, providing rigidity and resistance to fracture. Changes in the composition and organisation of these building blocks affect bone's mechanical integrity and can lead to some diseases of great public health concern, e.g. osteoarthritis, rickets and osteoporosis. Understanding the mineralisation process better will also allow a better understanding of soft tissue ossification abnormalities such as arterial calcification. The initiation of the first mineral crystals with the collagenous extracellular matrix is pivotal for ensuring that mineralisation progresses physiologically but unfortunately there are significant gaps in our knowledge on how this process occurs and is regulated. Therefore, this inter-disciplinary studentship will use various biology and chemistry approaches to determine how a protein (PHOSPHO1) essential for bone formation, regulates bone mineralisation and the establishment of the intimate relationship between the collagen and mineral phases. Ultimately this studentship will tell us how PHOSPHO1 regulates fibrillar collagen mineralisation.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M010996/1 01/10/2015 30/09/2023
1803936 Studentship BB/M010996/1 01/09/2016 31/08/2020 Scott Dillon
 
Description To date this studentship has generated new knowledge surrounding the biology of the PHOSPHO1 phosphatase (encoded by the Phospho1 gene) and its function in bone mineralisation during skeletal development. I have established that gene expression of Phospho1 and other phosphatases including Alpl (tissue non-specific alkaline phosphatase; TNAP) are correlated during skeletal development, and this coincides with changes in the expression of other mineralisation-related proteins. Both PHOSPHO1 and TNAP are expressed at sites which are actively mineralising during embryonic development and they are found in close proximity at the membranes of cells at these regions.

When PHOSPHO1 is genetically knocked-out, mineralisation of the developing skeleton is significantly reduced. I have examined these changes at the smallest scales using powerful electron microscopy and shown that this is due to an accumulation of small extracellular vesicles which, in the wild-type, are the initial locus of mineral formation. PHOSPHO1 is thought to reside inside these matrix vesicles and generate phosphate ions which are used to make mineral crystals. In the absence of PHOSPHO1 therefore mineral formation is much slower.

It is currently unknown how PHOSPHO1 substrates are generated inside matrix vesicles. I have introduced and validated a primary cell culture model of matrix vesicle production and isolation to our lab in order to investigate this question. I have so far established that the number of vesicles released by stimulated cells increases over time and contain both PHOSPHO1 and TNAP. Future studies will examine candidate proteins which may fit into the pathway upstream of PHOSPHO1.
Exploitation Route These studies surrounding the function of the PHOSPHO1 phosphatase have elucidated aspects of its basic biology and in doing so have opened potential therapeutic avenues for correcting a lack of mineralisation across a range of musculoskeletal conditions. Before treatments are realised however, further research is needed to fully explicate the PHOSPHO1 pathway of phosphate generation, and how it interacts synergistically with other mechanisms at play within and around the matrix vesicle. Interventions in these processes may be of interest in the healthcare and pharmaceutical sectors.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Biochemical Society Sponsored Event Grant
Amount £500 (GBP)
Organisation Biochemical Society 
Sector Learned Society
Country United Kingdom
Start 12/2018 
End 12/2018
 
Description Bone Research Society Sponsored Event
Amount £500 (GBP)
Organisation Bone Research Society 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2018 
End 12/2018
 
Description Roslin Institute Early Career Grant
Amount £1,414 (GBP)
Organisation University of Edinburgh 
Sector Academic/University
Country United Kingdom
Start 01/2019 
End 07/2019
 
Description Easter Bush Campus Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact We participated in the Easter Bush Campus Open Day 2017 which attracted hundreds of visitors across all age groups. Our activities surrounding bone biology provoked lots of questions and discussion, especially around musculoskeletal diseases of ageing such as osteoporosis and osteoarthritis.
Year(s) Of Engagement Activity 2017
URL https://www.ed.ac.uk/roslin/news-events/archive/2017/easter-bush-campus-open-day
 
Description Science Insights Sessions 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Students from local high schools were invited into our lab to do some hands-on bone histology, including staining and light microscopy, over two afternoons. The small group sizes enabled in-depth and wide-ranging discussions about the science, along with an exploration of career paths into science.
Year(s) Of Engagement Activity 2017,2018
URL https://www.ed.ac.uk/medicine-vet-medicine/outreach/science-insights