Biomarkers of Musculoskeletal Diseases: diagnosis & treatment of arthritis

Lead Research Organisation: Cardiff University
Department Name: School of Biosciences

Abstract

At present there are no biomarkers available that can definatively diagnose arthritis or measure the usefulness of many different treatment approaches that are available to help slow the progression of the disease and thereby improve the quality of life of the patient. Indeed, at present there are no means available to diagnose and distinguish between early stage rheumatoid arthtritis and early stage osteoarthritis; if this latter point could be achieved there would be substantial costs savings to the national health care providers in most countries worldwide. The objective of this proposal is to evaluate the capabilities of a panel of biomarker assays to detect different types of tissue breakdown or synthesis products in the blood, joint fluid and urine in large numbers of a medically well-characterised groups of patients with different stages in the progression and types of arthritic disease. These data will then be analysed for different patterns of expression of these substances with a view to identifying specific fingerprints of their occurrance that can be used in clinical trials, to diagnose different disease subtypes and also monitor the benefits of different treatment strategies. After these assays have been developed and validated using MRC funding these technologies will be transferred to an industrial partner so that they can become commercially available to hospitals and research institutions for use in clinical diagnosis and monitoring of treatments as well as for new drug discovery initiatives for treatment of arthritic diseases.

Technical Summary

The objectives of this proposal are to perform basic biomedical research (i.e. experimentation, development and validation), centred at Cardiff and Keele Universities, for the production and commercialisation (by our industrial partner, MD Biosciences) of robust ELISA kits that quantify body fluid biomarker expression patterns for numerous studies examining the aetiogenesis of degenerative joint diseases in humans. This proposal will focus on developing assays targeting proteoglycan analytes, matrix proteases and their degradation products. The assays to be developed and validated are: (i) new ELISAs that detect and quantify differences in keratan sulphate (KS) sulphation patterns on ?old? versus ?new? KS synthesised and released in different degenerative joint diseases and at different stages of the disease process; (ii) a new ELISA that quantifies the occurrence of aggrecanase-generated aggrecan analytes in biological fluids with an application to an ongoing clincal trial. Additional ELISAs detecting MMP-generated analytes and total aggrecan analyte will also be developed; (iii) the development of new and further development (for commercialisation) of existing ELISAs that quantify the expression of chondroitin sulphate (CS) sulphation motifs as anabolic or reparative biomarkers in degenerative joint disease; and (iv) new ELISAs that will quantify the presence of the serine proteinase HtrA-1 in synovial fluids. Once validated (using our large cohort of patient samples) ELISAs for established biomarkers (i.e. COMP, HA and CTX11) will also be undertaken. Collectively, the data from these studies will be used to elucidate biomarker expression patterns for use in drug discovery programmes, measuring outcomes of clinical trials, for diagnosis of disease and for measuring the efficacy of surgical, pharmaceutical or nutraceutical interventions.

Publications

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Brown S (2012) A comparative evaluation of the small leucine-rich proteoglycans of pathological human intervertebral discs. in European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society

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Caterson B (2012) Fell-Muir Lecture: chondroitin sulphate glycosaminoglycans: fun for some and confusion for others. in International journal of experimental pathology

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Hayes AJ (2013) Expression of glycosaminoglycan epitopes during zebrafish skeletogenesis. in Developmental dynamics : an official publication of the American Association of Anatomists

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Li S (2012) Proteoglycan metabolism, cell death and Kashin-Beck disease. in Glycoconjugate journal

 
Description 2014 Havemeyer Symposium on Equine Musculoskeletal Tissue Biomarkers
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
 
Description Havemeyer Foundation -Biomarkers for Musculoskeletal Diseases
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact Collectively, the contributors to this meeting were set the task of identifying and validating a variety of potential biomarker for musculoskeletal disease where there is a great deal of need for their use in clinical trials etc.
 
Description Arthritis Research UK - CS/DS as stem cell niche biomarkers
Amount £182,437 (GBP)
Organisation Versus Arthritis 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2011 
End 11/2014
 
Description Arthritis Research UK Tissue Engineering Centre (£6m across four centres - £2.5m ARUK/£3.4m HEIs)
Amount £825,000 (GBP)
Organisation Higher Education Funding Council for Wales (HEFCW) 
Sector Public
Country United Kingdom
Start 04/2011 
End 03/2016
 
Description Arthritis Research UK Tissue Engineering Centre (£6m across four centres - £2.5m ARUK/£3.4m HEIs)
Amount £625,000 (GBP)
Organisation Versus Arthritis 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2011 
End 03/2016
 
Description Charles Wolfson Studentship - Stem cell biomarkers in Disc
Amount £76,000 (GBP)
Organisation Charles Wolfson Charitable Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2009 
End 08/2012
 
Title BC-3-C2 
Description Biochemical maturation was performed on one of our existing monoclonal antibodies (BC-3) to increase its affinity and then potential use in liquid phase biomarker assays; e.g. ELISAs. Ely Lilly have now produced an antibody (BC-3-C2) that has several orders of magnitude higher affinity than our original mAb BC-3. 
Type Of Material Antibody 
Provided To Others? No  
Impact Researchers at Ely Lilly have now published work showing that this new 'matured' monoclonal antibody can be used in ELISA-based assays to detect aggrecanase-generated analytes (with the neoepitope ARG...) in synovial fluids, sera and urine from patients suffering a variety of different arthritic diseases. 
 
Title Chipman - live cell quantification 
Description Development of biomarkers to quantify live cell morphology 
Type Of Material Data analysis technique 
Provided To Others? No  
Impact Preliminary results for future research and submission of grant applications. 
 
Title MesoScale Diagnostics (MSD) Assay methods 
Description MesoScale Diagnostics have developed and commercialised a very sensitive assay system for multiplex assays of body fluids (sera/plasma, synovial fluid & urine) as well as tissue samples. To date we have tested several of our mAbs in this system and the results look very promising for the development of new assays. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact This new technology will provide very sensitive assay procedures where we can analyse large numbers of patient samples for different analyte compositions and thereby obtain "finger prints" or "signatures" of analyte patterns that can be used in disease diagnosis and/or determning the efficacy of treatments (therapeutic or clinical) for patients. 
 
Title Use of CNBr hydrolyses to analyse proteoglycan metabolism. 
Description CNBr cleavage hydrolyses most if not all extracellular matrix proteins. Thus, CNBr was used to hydrolyse various different proteoglycans from musculoskeletal tissues with high collagen contents; e.g. tendons. This method allows quantitative analyses of metabolic changes in these molecules in health and disease. 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact in the past, the use of chemical extraction procedures (e.g. guanidine HCl extraction) only allowed one to analyse changes in the metabolism of selected proteoglycan population in highly collagenous tissues. Our new method allows this to be done on most if not all of those present in a given tissue. 
 
Description Arthritis Research UK Biomechanics & Bioengineering Centre 
Organisation Cardiff University
Department School of Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We are both consultants and collaborators for this Centre Grant. We share patient samples and provide antibodies for biomarker and other analyses.
Collaborator Contribution We have preliminary data on biomarker assays that have and will be used in new grant applications
Impact Obtaining preliminary data for submission of new grant applications.
Start Year 2010
 
Description Dr Nancy Pleshko - ST-IRIS applications to identifying Cartilage Repair biomarkers 
Organisation Temple University
Country United States 
Sector Academic/University 
PI Contribution Oswestry provides well-characterised clinical patient samples for analyses using these novel infra-red applications.
Collaborator Contribution Provision of preliminary data for use in new grant applications.
Impact Have obtained preliminary data for use in new grant applications and plan to prepare data for publication.
Start Year 2010
 
Description Novel methods for studying proteoglycan metabolism in Tissues. 
Organisation University of Sydney
Department Kolling Institute
Country Australia 
Sector Academic/University 
PI Contribution Together we developed new ways (CNBr hydrolysis) of solubilising all/most of the proteoglycans from very collagenous musculoskeletal tissues (e.g. tendon) and developed ways to identify biomarker patterns as their metabolism changes with health and disease.
Collaborator Contribution Since returning from my 3 month sabbatical I have submitted a Project Grant application to Arthritis Research UK using data collected on this mini-sabbatical.
Impact Submission of an application for a Project Grant from Arthritis Research UK.
Start Year 2009
 
Description The glycobiology of the stem/progenitor cell niche 
Organisation University of Sydney
Department Kolling Institute
Country Australia 
Sector Academic/University 
PI Contribution Preliminary studies on developing musculoskeletal tissues using monoclonal antibodies that recognise chondroitin sulphate sulphation motifs to determine their specific expression patterns during development and ageing.
Collaborator Contribution Papers in preparation and submission of a grant application to the Mizutani Foundation in Japan.
Impact Preparation of papers and the submission of a grant application to the Mizutani Foundation, Japan
Start Year 2009
 
Description University of Reading - Cornea Biomarkers 
Organisation University of Reading
Department School of Pharmacy Reading
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of ELISA-based biomarker assays
Collaborator Contribution Our collaborators are attempting to produce tissue-engineered corneas for use in patient transplants. We are providing well-characterised antibodies for their use in ELISA-based assays to assess the expression of appropriate biomarkers of corneal development. This data will be used in future publications.
Impact This grant has only just started.
Start Year 2011
 
Description League of Friends - Wales 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact 20 -50 audiences: Lay description of ongoing medical research projects.

These meetings afford an opportunity for the lay public to find out more about current biomedical research in the area of musculoskeletal diseases.
Year(s) Of Engagement Activity 2011
 
Description Lectures to Health Professionals 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Health professionals
Results and Impact 20-50 MSc Physiotherapists - they get a better understanding of molecular events that lead to musculoskeletal diseases.

Good questions asked at the end of the lectures and hopefully they get a better understanding of molecular mechanisms underpinning the onset and treatment of musculoskeletal diseases.
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011
 
Description Local Schools 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact Sparked interesting questions and discussion regarding current medical research.

Students came to visit the Oswestry Research labs.
Year(s) Of Engagement Activity 2009,2011
 
Description Nuffield & GCSE Work experience students 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Primary Audience Schools
Results and Impact Students got experience at state of the art research methods related to their future academic goals.

They worked in an active biomedical research lab.
Year(s) Of Engagement Activity 2011
 
Description Nutraceutical Lectures 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact Lectures to audiences of 50 - 100 to discuss the pros and cons of dietary nutraceutical supplements for treatment of musculoskeletal diseases.

Lots of questions on the biological mechanisms underlying the use of nutraceutical supplements to prevent or slow down the course of musculoskeletal diseases.
Year(s) Of Engagement Activity 2011
 
Description School Education day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Primary Audience Schools
Results and Impact ~50 school children (mostly sixth formers who were interested in a career in science) attended an Open Day organised by 3 staff in the hospital, including one of the grant holders.
Lectures and practical sessions were organised throughout the researh laboratories.

The day was prompted by a scheme run by the Pathological Society but it proved very sucessful with pupils attending from ~6 local schools and sixth form colleges.
Year(s) Of Engagement Activity 2009