Investigating Yap as a Novel Therapeutic Target for Rheumatoid Arthritis

Rheumatoid arthritis (RA) is the most common chronic inflammatory disease in the UK, affecting ~1% of adults. It mainly affects the joints and can progress rapidly, causing joint damage and devastating deformities. The total costs associated with RA have been estimated to be up to £6 billion per year in the UK. Research has mostly focussed on understanding the role of the immune system and inflammation in RA and how we can suppress this, which has led to important advances in treatment in recent years with the biologics. However, two major problems remain unresolved: (i) up to 30% of patients fail to respond to treatments, and (ii) joint damage can still occur even when inflammation is successfully treated, suggesting that suppression of inflammation alone is not sufficient to stop disease progression and fully treat RA.
A key feature of RA is inflammation of the synovial membrane (synovitis). This membrane covers the inside of the joint or joint cavity. During RA, the synovial membrane becomes thicker and forms a so-called "pannus" that is causing the destruction of cartilage and bone. The pannus is considered like a tumour that results from uncontrolled growth of cells in the membrane. We want to understand what drives this process, and find out ways to stop this.
We have discovered that a particular protein, called Yap, is very high in the synovial membrane during arthritis. This protein is known in other tissues and organs, including liver, intestine, skin and brain, to stimulate tissue/organ growth. We therefore think that Yap may drive the synovial pannus overgrowth in RA. We will investigate this by using a model in which we can activate Yap in cells in the synovial membrane, and we will determine whether this causes cells in the membrane to overgrow and form a pannus similar to what happens during RA. To this end, we will combine and refine existing models and techniques available in our laboratory.
We also want to know if we can prevent or reduce the RA pannus by blocking the activity of Yap. We will investigate this by inactivating the Yap gene in the cells of the synovial membrane, so that cells can no longer make the Yap protein. We will do this in our model of RA available in our laboratory and determine whether this can prevent or reduce pannus formation and cartilage and bone destruction. Finally, we will investigate if a drug that has recently been discovered to block the activity of Yap could be used to treat RA.
These studies will increase our understanding of the formation of the pannus and resulting cartilage and bone destructions in RA, and identify a new therapeutic target for the treatment of RA.

Rheumatoid arthritis (RA) causes devastating joint damage. Despite significant therapeutic advances, two major problems remain unresolved: 1) up to 30% of patients fail to respond to treatment; 2) progression of joint damage can occur even when clinical remission is achieved, suggesting that joint destruction and inflammation are at least partly uncoupled.
Hallmark of RA is synovitis, with pathological outgrowth of synovium (pannus) sustained by proliferation of mesenchymal stem cells/fibroblast-like synoviocytes (MSC/FLS). The pannus is a tumour-like structure resulting from uncontrolled tissue growth. A key molecular pathway that controls tissue growth is the Hippo pathway, restricting the activity of Yes-associated protein (Yap). Our preliminary findings indicate that (i) Yap expression is high in MSC/FLS in inflammatory arthritis and (ii) high levels of Yap activity cause MSC/FLS proliferation. We hypothesise that Yap is a key player in the stromal cell expansion during synovitis leading to pannus formation.
To investigate whether Yap activation in synovial stromal cells causes pannus formation and induces an RA-like invasive MSC/FLS phenotype, we will generate transgenic mice in which expression of constitutively active Yap is Dox-inducible in stromal cells in the joint. Conversely, to determine whether Yap inhibition in the synovium ameliorates arthritis, we will use Yap-flox mice to knockout Yap in the antigen-induced arthritis. Finally, we will explore pharmacological targeting of Yap in arthritis by administering a recently identified Yap inhibitor. We will use our established double-nucleoside-labelling scheme to investigate proliferation of MSC/FLS in synovium, and will assess synovial pannus formation and erosions. We will also assess invasiveness of the MSC/FLS ex vivo following Yap activation or inhibition.
In conclusion, this study will elucidate the role of Yap in pannus formation and provide proof-of-concept of Yap as a therapeutic target for RA.

The societal impacts of this work are most likely to lie beyond the three years of this project but can potentially be enormous. Rheumatoid arthritis (RA) causes debilitation to the affected people and poses challenges to the society. There are ~400,000 people with RA in the UK, and ~12,000 people of all ages develop RA per year in the UK. Approximately one-third of people stop work because of the disease within 2 years of onset, and this prevalence increases thereafter. Clearly this disease is costly to the UK economy, to the NHS and to individuals. The project will entail fundamental and preclinical research important to (i) further our understanding of the pathogenesis of RA and (ii) develop novel therapeutic approaches to slow down or even arrest disease progression. Our research would benefit patients in the UK and worldwide, who could receive tailored treatments thus improving health, permitting them to continue functioning normally for longer and increasing quality of life. Long-term, this will thus benefit the UK NHS and society globally by reducing the disability-related economic costs (e.g. reducing incapacity benefit and associated costs of care, and increasing work capacity of the individuals).

To maximise impact of our research, during the project we will communicate the findings as they become available to stakeholders at national and international conferences that are attended by scientists, clinicians, patient organisations and media (e.g., EULAR), and publish the results in a timely manner in international journals. We will explore clinical applicability also through regular discussions of our research findings within the NHS Clinical Rheumatology Department. In this regard, the weekly educational meetings in the NHS Rheumatology Department enable discussion of research findings in the clinical context, thereby providing invaluable guidance on clinical translation.

Commercial exploitation will be required to facilitate the clinical translation of the findings, ultimately into a routine clinical therapy. To pursue any potential translational or commercial opportunities of our work, we will seek assistance from the Kosterlitz Centre for Therapeutics at the University of Aberdeen, an organisation that provides links between academics, industrial partners and the business sector. To further facilitate exploitation and application of the planned research and to help in IP issues, we will also work with the Research and Innovation Department at the University of Aberdeen. Potential opportunities for commercialisation will be reviewed regularly throughout the project.

The researchers employed on this grant will be direct beneficiaries of this project (short and long term). They will gain professional experience and skills relevant for the development of a career in research. It will enhance their employability and contribute to the economic competitiveness of the UK. Recruitment of the postdoc will contribute to the health of the wider musculoskeletal research community (short and long term) by bringing a new generation of researchers into this field. Similarly, training of a research technician will contribute to ensure sustainability within the field.

An immediate impact is the opportunity to raise public awareness and understanding of biomedical research. Throughout the project, we will engage with the public by (i) publishing the results in high-impact journals with Open Access Compliant policies; (ii) making use of the University of Aberdeen Communications Office as well as the MRC Press Office services to disseminate our findings as widely as possible; (iii) by continuing our outreach activities aimed at children and adults (e.g. Techfest and Café Med).