Unravelling functional cartilage repair in osteoarthritis: a multidisciplinary approach

PROJECT OVERVIEW

Although previously regarded as a tissue with little intrinsic repair, even severely damaged articular cartilage is able to regenerate, given the correct biomechanical joint environment and availability of repair factors. The best evidence of repair capacity to date comes from patients undergoing the surgical procedure of joint distraction, where a metal external frame is applied to “off-load” the joint for a period of 6 weeks. After 6 weeks the frame is removed and the patients are rehabilitated. Results from cohorts of individuals undergoing joint distraction show rapid improvement in pain and function, as well as evidence of regrowth of cartilage in the severely damaged regions of the OA joint (by MRI) (Wiegant et al. 2013).

Work from the Vincent laboratory has uncovered a key mechanism by which growth factors, released following compressive load, coordinate intrinsic repair of articular cartilage. Five matrix-bound growth factors have been identified to date. They are sequestered in the pericellular matrix of cartilage and when released, drive a coordinated, temporally controlled, repair process. Two of these growth factors: FGF2 and connective tissue growth factor (CTGF), which is covalently bound to TGFb (TGFb), are important in the initiation (FGF2) and termination (TGFb) of the repair response (Tang et al. 2018; Chia et al. 2009). Both TGFb and FGF2 protein increase (10-100 fold) in the synovial fluid of individuals with OA over the course of joint distraction (Watt et al. 2020). Much less is known about the other pericellular growth factors, how they contribute to repair and their cellular mechanism of action.

The STEpUP OA is a large international Consortium project in which proteomic profiling (using Somascan technology, >7000 proteins) has been performed on over 1500 individuals with knee osteoarthritis (Deng et al. 2023). Within the larger cohort is the group (n=18) of individuals whose synovial fluid had been sampled before and after joint distraction. These samples have been analysed using Somascan and are now ready to interrogate.

The purpose of this project will be to:

1. Analyse the proteins and pathways regulated in the OA joint following distraction
2. Determine the overlap between these pathways and those molecules/pathways that are driving cartilage repair identified using pre-clinical models.
3. Define a “repairing” signature which could be applied to the wider OA population within STEpUP OA to determine whether this affects disease severity and the course of disease.
4. Use a combination of wet lab and dry lab techniques to explore further the function of pericellular matrix bound growth factors in the repair response.

KEYWORDS (5 WORDS)

Osteoarthritis, cartilage repair, STEpUP OA, growth factors, SomaLogic

TRAINING OPPORTUNITIES

This project is well suited to a student with an interest in combining both wet and dry laboratory investigations to uncover how cartilage repairs.

The successful candidate will be benefit from supervision by a team of scientists with key expertise in OA biology, preclinical models, bioinformatics and integration of large clinical datasets. You will be based in the Kennedy Institute of Rheumatology, a world-leading centre for translational research. You will be embedded within a multidisciplinary laboratory of dry and wet lab trainees, post docs and clinician scientists as part of our larger Centre for OA Pathogenesis. Training will be provided in data science techniques including statistical data analysis and visualisation with R, the writing of computational pipelines with Python/NextFlow, and the use of high-performance compute clusters.

The Kennedy Institute is a world-renowned research centre and has a vibrant PhD program with weekly journal club, seminars, student symposia, weekly internal institute presentations and training. A core curriculum of lectures will provide a solid foundation of a broad range of subjects including data analysis, statistical methods, and osteoarthritis pathogenesis. In additional to institutional support, the successful applicant will benefit from being part of the University of Oxford college system.

KEY PUBLICATIONS (5 MAXIMUM)

Chia, Shi-Lu, Yasunobu Sawaji, Annika Burleigh, Celia McLean, Julia Inglis, Jeremy Saklatvala, and Tonia Vincent. 2009. "Fibroblast Growth Factor 2 Is an Intrinsic Chondroprotective Agent That Suppresses Adamts-5 and Delays Cartilage Degradation in Murine Osteoarthritis." Arthritis and rheumatism 60, no. 7 (Jul): 2019-2027. https://dx.doi.org/10.1002/art.24654.

Deng, Y., T.A. Perry, P. Hulley, R.A. Maciewicz, J. Mitchelmore, D. Perry, S. Larsson, S. Brachat, A. Struglics, C.T. Appleton, S. Kluzek, N. K. Arden, D. Felson, B. Marsden, B.D.M. Tom, L. Bondi, M. Kapoor, V. Batchelor, J. Mackay-Alderson, V. Kumar, L. S. Lohmander, T. J. Welting, D. A. Walsh, A.M. Valdes, the STEpUP OA Consortium, T. L. Vincent, F. E. Watt, and L Jostins-Dean. 2023. "Methodological Development of Molecular Endotype Discovery from Synovial Fluid of Individuals with Knee Osteoarthritis: The Stepup Oa Consortium." BioRxiv preprint. https://dx.doi.org/https://doi.org/10.1101/2023.08.14.23294059.

Tang, Xiaodi, Hayat Muhammad, Celia McLean, Jadwiga Miotla-Zarebska, Jacob Fleming, Athanasios Didangelos, Patrik Önnerfjord, Andrew Leask, Jeremy Saklatvala, and Tonia L Vincent. 2018. "Connective Tissue Growth Factor Contributes to Joint Homeostasis and Osteoarthritis Severity by Controlling the Matrix Sequestration and Activation of Latent Tgfβ." Annals of the rheumatic diseases  (Jun 20). https://dx.doi.org/10.1136/annrheumdis-2018-212964.

Watt, F. E., B. Hamid, C. Garriga, A. Judge, R. Hrusecka, R. J. H. Custers, M. P. Jansen, F. P. Lafeber, S. C. Mastbergen, and T. L. Vincent. 2020. "The Molecular Profile of Synovial Fluid Changes Upon Joint Distraction and Is Associated with Clinical Response in Knee Osteoarthritis." Osteoarthritis Cartilage 28, no. 3 (Mar): 324-333. https://dx.doi.org/10.1016/j.joca.2019.12.005

Wiegant, K, P M van Roermund, F Intema, S Cotofana, F Eckstein, S C Mastbergen, and F P J G Lafeber. 2013. "Sustained Clinical and Structural Benefit after Joint Distraction in the Treatment of Severe Knee Osteoarthritis." Osteoarthritis and Cartilage 21, no. 11 (Nov): 1660-1667. https://dx.doi.org/10.1016/j.joca.2013.08.006.

THEMES: (4 KEY THEMES)

Computational biology, proteomics, osteoarthritis

CONTACT INFORMATION OF ALL SUPERVISORS

Email tonia.vincent@kennedy.ox.ac.uk