Suppressing mechanoflammation in osteoarthritis by targeting apoptosis-signal regulating kinase-1

PROJECT OVERVIEW 

The cellular basis of osteoarthritis (OA) remains incompletely understood. The most important aetiological factor in OA development is mechanical stress, so how the tissues of the joint respond to mechanical stress is likely to be important in disease. Over 20 years the Vincent lab has shown that the articular chondrocytes, the principal cells of cartilage, respond in two distinct ways to mechanical stimulation: compression of the tissue results in release of growth factors that are protective and pro-regenerative. The second trigger is excessive shear stress at the articular surface which drives a process that we have termed "mechanoflammation" because it is sufficient to activate inflammatory signalling and drive inflammatory gene regulation. Inhibition of mechanoflammation is predicted to suppress degradation of the cartilage in disease and restore homeostasis.

Recent unpublished work from our lab has identified a mitogen activated protein kinase kinase kinase (MAPKKK) called apoptosis-signal regulating kinase-1 (ASK1) which is up-stream of the MAPKs and inflammatory gene regulation. ASK1 is classically activated by reactive oxygen species (ROS) and accordingly, we showed that suppressing ROS activity in the tissue is also able to prevent the downstream inflammatory consequences. Interestingly ASK1 inhibitors have been tested extensively in other disease areas but never in OA. The drugs are well tolerated and safe.

In this proposal, we will test the hypothesis that inhibition of ASK1 is disease modifying in murine OA and explore the mechanism by which ROS are generated by cartilage injury. Using in vitro and in vivo systems, this studentship will:

• Explore the molecular pathway by which cartilage injury leads to generation of mitochondrial ROS to trigger mechanoflammation.
• Understand how cellular metabolism switches after injury from glycolysis to oxidative phosphorylation and how important this is for the injury response.
• Test the disease modifying effects of an ASK1 inhibitor, selonsertib, in vivo in a well validated model of murine OA.

KEYWORDS 

Osteoarthritis, reactive oxygen species, mitochondria, ASK1, mechanoflammation

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 osteoarthritis and on mitochondrial dysfunction and metabolism in disease.
The student 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 normal porcine cartilage 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 techniques available in-house, including tissue culture, phosphoproteomics, OA models, cell imaging.
• Strong translational environment: the findings from this study may develop into an Experimental Medicine study in which to validate ASK1 inhibitors 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 beyond. 

KEY PUBLICATIONS 

1. Vincent, T.L., O. McClurg, and L. Troeberg, The Extracellular Matrix of Articular Cartilage Controls the Bioavailability of Pericellular Matrix-Bound Growth Factors to Drive Tissue Homeostasis and Repair. Int J Mol Sci, 2022. 23(11).
2. Vincent, T.L., Of Mice and Men; converging on a common molecular understanding of Osteoarthritis. Lancet Rheumatology, 2020. 2(10): p. E633-E645, .
3. Vincent, T.L., Mechanoflammation in osteoarthritis pathogenesis | Elsevier Enhanced Reader. Seminars in arthritis and rheumatism, 2019. 49: p. S36-38.
4. Ismail, H.M., et al., Brief Report: JNK-2 Controls Aggrecan Degradation in Murine Articular Cartilage and the Development of Experimental Osteoarthritis. Arthritis & rheumatology (Hoboken, N.J.), 2016. 68(5): p. 1165-1171.
5. Harrison, S.A., et al., Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials. J Hepatol, 2020. 73(1): p. 26-39. 

KEY THEMES 

Translational medicine, arthritis, cell biology