Biomarkers of Musculoskeletal Diseases: diagnosis & treatment of arthritis

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.

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.