Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

  • Project No: Clinical-1
  • Intake: 2024 KIR Clinical

PROJECT OVERVIEW

The cellular basis of osteoarthritis (OA) remains enigmatic. Pathogenesis in OA is in part due to loss of articular cartilage driven by direct sensing of chondrocytes to mechanical stress [1]. However, people with OA also have synovial inflammation (synovitis) and fibrosis, which correlates with disease severity and symptoms. The importance of the synovium in disease initiation and progression is unclear. The synovitis in OA is very distinct from synovitis in RA as it is low-grade, with low levels of the typical inflammatory markers observed in rheumatoid arthritis (RA) and associated with cytokines typically seen in fibrotic conditions. Like the articular cartilage, the synovium is also highly mechanosensitive. Together this has led to the concept that OA is a disease of ‘mechanoflammation’; inflammation directly triggered by mechanical as opposed to soluble inflammatory stimuli [2].  

Acute destabilising injuries of the joint lead to mechanoflammation and are common after sporting injuries (such as rugby and football). These confer a greatly enhanced risk of developing OA within 5-10 years [3]. OxKIC is a knee injury cohort in Oxford, in which synovial biopsies and clinical data have been collected prospectively in around 100 individuals.  The team also have access to a small number of normal healthy synovial samples.

The healthy synovium consists of two distinct anatomical compartments: a thin lining layer (LL) and a thicker sub-lining layer (SL). In health, the synovium is devoid of lymphocytes and consists of specialised synovial fibroblasts, adipocytes, endothelial cells as well as tissue-resident macrophages. GDF5 positive stem cells are also thought to derive from the synovium after joint injury. Although synovial pathology in OA remains poorly defined by comparison with normal healthy tissue, recent findings, including our own, have revealed cell types that are significantly expanded within OA compared with RA synovium. For example, FAP+CD90+ sub-lining fibroblasts are enriched in RA compared with OA synovium. In complete contrast, FAP+CD90- lining fibroblasts are expanded in OA compared with RA [4] (Figure below). A comparison of OA samples with normal synovium is an important gap in our current knowledge.  As are the early changes that occur in the synovium after joint injury.

Expansion of lubricin+ CD90 negative lining fibroblasts in OA, compared to CD90+ sub lining fibroblasts in RA. CD146 is a mural cell marker found surrounding blood vessels  Expansion of lubricin+ CD90 negative lining fibroblasts in OA, compared to CD90+ sub lining fibroblasts in RA. CD146 is a mural cell marker found surrounding blood vessels

As LL fibroblasts derive from a shared ancestry, share many similarities with superficial chondrocytes, for example lubricin production, and are contiguous with the articular surface, in this project we will test the hypothesis that LL synovial fibroblasts, along with articular chondrocytes, contribute to OA pathogenesis. Using a combined human and mouse approach this studentship will:

1      Define the cellular and tissue structural differences between normal and osteoarthritic human synovium.

2      Explore the synovial histology at early points post joint injury and relate these to patient symptoms and outcome.

3      Determine the effects of deleting either LL fibroblasts and/or articular chondrocytes in well-established animal models of OA using transgenic cell deletion strategies (fibroblast/chondrocyte Cre drivers crossed with inducible DTR mice)

KEYWORDS (5 WORDS)

Arthritis, fibroblast, chondrocyte, single cell RNA-sequencing, animal models

TRAINING OPPORTUNITIES

The successful candidate will be embedded within the Centre for OA Pathogenesis Versus Arthritis at the Kennedy Institute of Rheumatology, Oxford. They will benefit from supervision by an experienced team of clinician scientists interested in the cell biology of arthritis and deeply involved in clinical studies including drug induced perturbation studies. They will work closely with Kluzek (Institute for sports medicine Nottingham), as well as two collaborators  with expertise in human OA tissue and biomaterials based in the Botnar Centre, Oxford.

You will be based in the laboratories of the Kennedy Institute of Rheumatology, a world-leading centre in the fields of tissue biology, inflammation, and repair, with a strong emphasis on clinical translation. The project will use a combination of human OA tissue samples and murine models of arthritis. There is support available from post-doctoral scientists and laboratory managers in our groups. In summary, you will be working within:

  • Cutting-edge cell biology and next generation sequencing techniques available in-house, including tissue culture, cell sorting, arthritis models, multi-channel immunohistochemistry and single cell RNA-sequencing analysis
  • Strong translational environment: findings from human and murine samples in conjunction with next generation sequencing to define and test putative therapeutic targets in OA  
  • Well-established DPhil programme with defined milestones, ample training opportunities within the University and Department, and access to university/department-wide seminars by world-leading scientists
  • Highly collaborative environment with expertise ranging from molecular and cell biology to in vivo models and computational biology / genomics analysis. You will also have the opportunity to participate in several other collaborations within the University of Oxford and with the Universities of Nottingham and Birmingham

KEY PUBLICATIONS (5 MAXIMUM)

1.         Vincent, T.L., Of Mice and Men; converging on a common molecular understanding of Osteoarthritis. Lancet Rheumatology, 2020. 2(10): p. E633-E645, .

2.         Vincent, T.L., Mechanoflammation in osteoarthritis pathogenesis | Elsevier Enhanced Reader. Seminars in arthritis and rheumatism, 2019. 49: p. S36-38.

3.         Lohmander, L.S., et al., The long-term consequence of anterior cruciate ligament and meniscus injuries: osteoarthritis. The American journal of sports medicine, 2007. 35(10): p. 1756-1769.

4.         Croft, A.P., et al., Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature, 2019. 570(7760): p. 246-251. 

THEMES: (4 KEY THEMES)

Translational medicine, arthritis, systems biology and genomics

CONTACT INFORMATION OF ALL SUPERVISORS

tonia.vincent@kennedy.ox.ac.uk

christopher.buckley@kennedy.ox.ac.uk