Exploring the cellular contribution of fibroblasts and chondrocytes in osteoarthritis pathogenesis
- Project No: KIRC2
- Intake: 2022 KIR Clinical
Supervisor: Prof. Tonia Vincent
Co-Supervisors: Prof. Chris Buckley, Dr Stefan Kluzek (University of Nottingham), Dr Jolet Mimpin, Prof. Sarah Snelling
The cellular basis of osteoarthritis (OA) remains enigmatic. Pathogenesis in OA has traditionally been ascribed to loss of articular cartilage driven by mechanical stress. However, emerging studies have shown that people with OA have synovial inflammation (synovitis) and fibrosis. Imaging techniques have confirmed synovitis at many stages in the progression of OA. Furthermore, histological and imaging synovitis appears to be related to pain, poor function, and progression of radiographic OA. Interestingly, these synovial changes appear in some cases to precede cartilage damage, suggesting that they are not necessarily secondary to underlying cartilage damage. 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. This has led to the concept that OA is a disease of mechano-inflammation; inflammation associated with mechanical as opposed to inflammatory stimuli. 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. Although synovial pathology in OA remains poorly defined by comparison to RA, recent findings, including our own, have revealed cell types that are significantly expanded within OA compared to RA synovium. For example, FAP+CD90+ sub-lining fibroblasts are enriched in the RA compared to OA synovium. In complete contrast, FAP+CD90- lining fibroblasts are expanded in OA compared to RA 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:
- Define the cellular and tissue structural differences between normal and osteoarthritic human synovium.
- Explore the synovial histology at early points post joint injury and relate these to patient symptoms and outcome.
- 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)
Arthritis, fibroblast, chondrocyte, single cell RNA-sequencing, animal models
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
- Vincent, T.L., Of Mice and Men; converging on a common molecular understanding of Osteoarthritis. Lancet Rheumatology, 2020. 2(10): p. E633-E645, .
- Vincent, T.L., Mechanoflammation in osteoarthritis pathogenesis | Elsevier Enhanced Reader. Seminars in arthritis and rheumatism, 2019. 49: p. S36-38.
- 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.
- Croft, A.P., et al., Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature, 2019. 570(7760): p. 246-251.
Translational medicine, arthritis, systems biology and genomics,
Prof. Tonia Vincent