How does ageing influence intrinsic cartilage repair in osteoarthritis?

Articular cartilage breakdown is a hallmark of osteoarthritis (OA), the highly prevalent joint disease of ageing. 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. The best evidence of repair 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) [1].

Using a combination of in vitro models, in vivo models and large-scale human OA synovial fluid protein profiling (from the STEpUP OA Consortium [2]), including before and after joint distraction, the Vincent laboratory has uncovered the mechanism by which cartilage repairs itself. This is mediated by growth factors, that are released from the cartilage matrix following excessive mechanical load and result in the mobilisation and proliferation of chondroprogenitor cells (CPCs). Five matrix-bound growth factors have been identified by us to date and each has a role in this coordinated response. Two of these growth factors: FGF2 and connective tissue growth factor (CTGF), which is covalently bound to TGFb display chondroprotective roles in vivo [3, 4]. Growth factors are released together through a common mechanism [5], but much less is known about their role, how they contribute to repair and their cellular mechanisms of action.

One important caveat to our discovery is that the intrinsic cartilage repair mechanism has largely been validated in young healthy tissue. It is likely that the efficiency of repair will decrease with age and contribute to the marked increase in OA that is seen in older populations. How and at which stage in the repair cycle ageing influences repair is important to understand if we are to design therapeutic approaches to help patients with OA.

The purpose of this project will be to:

1. Explore the functional role of specific growth factors in young and older murine joints using established in vivo tools in genetically modified mice (mice already available).
2. Test whether CPCs isolated from human OA tissue (typically aged) are similarly responsive to those generated from young (porcine) tissue.
3. Interrogate the human synovial fluid proteome in STEpUP OA (derived from 1400 patient samples) to explore growth factor/repair related pathways and how these are influenced by patient age. 

KEYWORDS

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

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, ageing 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. Where necessary, training will be provided in data science techniques..

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

1.         Wiegant, K., et al., Sustained clinical and structural benefit after joint distraction in the treatment of severe knee osteoarthritis. Osteoarthritis and Cartilage, 2013. 21(11): p. 1660-1667.

2.         Perry, T.A., et al., Deconvoluting synovial fluid molecular endotypes in knee osteoarthritis: primary results from the STEpUP OA Consortium. 2024.

3.         Tang, X., et al., 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, 2018.

4.         Chia, S.-L., et al., Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS-5 and delays cartilage degradation in murine osteoarthritis. Arthritis and rheumatism, 2009. 60(7): p. 2019-2027.

5.         Keppie, S.J., et al., Matrix-Bound Growth Factors are Released upon Cartilage Compression by an Aggrecan-Dependent Sodium Flux that is Lost in Osteoarthritis. Function (Oxf), 2021. 2(5): p. zqab037.

THEMES

Computational biology, stem cell biology, proteomics, osteoarthritis,

CONTACT INFORMATION OF ALL SUPERVISORS

tonia.vincent@kennedy.ox.ac.uk

ghada.alsaleh@ndorms.ox.ac.uk

The Kennedy Institute is a proud supporter of the Academic Futures scholarship programme, designed to address under-representation and help improve equality, diversity and inclusion in our graduate student body.  The Kennedy and the wider University rely on bringing the very best minds from across the world together, whatever their race, gender, religion or background to create new ideas, insights and innovations to change the world for the better. Up to 50 full awards are available across the three programme streams, and you can find further information on each stream on their individual tabs (Academic futures | Graduate access | University of Oxford).

How to Apply

Please contact the relevant supervisor(s), to register your interest in the project, and the departmental Education Team (graduate.studies@ndorms.ox.ac.uk), who will be able to advise you of the essential requirements for the programme and provide further information on how to make an official application.

Interested applicants should have, or expect to obtain, a first or upper second-class BSc degree or equivalent in a relevant subject and will also need to provide evidence of English language competence (where applicable). The application guide and form is found online and the DPhil or MSc by research will commence in October 2025. 

Applications should be made to the following programme using the specified course code.

D.Phil in Molecular and Cellular Medicine (course code: RD_MP1) 

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford.

Interviews to be held week commencing 13^th January 2025.