Development and clinical validation of novel biomarker assays for osteoarthritis

Osteoarthritis (OA) is one of the most common chronic diseases affecting the adult population. Currently, definitive diagnosis of OA is usually made using plain x-rays at relatively advanced stages of the disease when there is irreparable damage to the joint(s). We and others have demonstrated that serum levels of macromolecules (biomarkers) can provide a way identifying patients with early OA and those likely to progress. However, currently available biomarkers lack specificity and sensitivity to pick up individual patient from control or identify a patient who will progress over time. Therefore there is an urgent need to seek novel and more specific-biomarkers for investigation of OA and other joint diseases. The discovery of OA-specific biomarkers offers the potential for early diagnosis and therefore more effective management of the condition. Our recent proteomic studies(1) have identified 4 novel biomarkers for OA, 3 of which have been identified by mass spectromerty as V65 Vitronectin, complement C3f and connective tissue-activating peptide III (CTAPIII). The aim of the proposed study is to carry out full biochemical characterization including peptide sequencing of the fourth biomarker and develop new assays for two of the biomarkers (V65) and C3f). Serum samples from existing OA cohorts as well as samples from healthy and disease control groups will be used for clinical validation of the biomarker assays.

The PhD student will develop novel biomarker assays using panels of monoclonal and polyclonal antibodies already available in our laboratory, and carry our validation of these assays using serum samples already collected from patients and controls. The project will also involve the use of monoclonal and polyclonal antibodies to the novel biomarkers for immuno-localization of these peptides (biomarkers) in joint tissues, and relate these measurements to concentrations of the biomarkers in blood and key x-ray and MRI features of the disease. The project is in collaboration with the National Institute of Health in USA, and serum samples and patients’ clinical data will be obtained from the NIH osteoarthritis biomarker initiative. Our laboratory is in the Faculty of Medicine and Dentistry at the University of Bristol, and the PhD will work as part of a team involved in application of biomarkers to explore the mechanisms of development and progression of knee OA.

The PhD candidate should have basic knowledge/experience of enzyme-linked immunosorbent assays (ELISA), handling clinical and imaging data (x-ray and MRI) from large numbers of patients and able to apply appropriate statistical tests to analyse the data.

All the equipment and methodologies required for this project are already in place in the musculoskeletal research laboratories at the School of Clinical Sciences. Moreover, we have a steady supply of OA and control cartilage from total joint replacement surgery (from the Avon Arthopaedic Centre) and cadavers (from Anatomy DR at Southwell Street) which would be used for histological analyses/grading of the OA cartilage and related to measurements of
the novel biomarkers in the patients.