Osteoarthritis: Going back to basics

Have you ever experienced an aching pain in your joints when you stand up? Or stiffness after periods of rest? Throughout life, our joints change continuously and adapt to the varying and often huge demands placed upon them as we walk, run, lift and jump. However, as we get older our joints undergo structural changes that may lead to the aching and stiffness that is often associated with ageing.

Osteoarthritis is the most important ageing-related disease affecting almost 9 million people in the UK. It is estimated that more than 33% of the UK population aged over 45 have sought treatment for osteoarthritis. For this reason, osteoarthritis is a major financial, social and healthcare burden. Current osteoarthritis treatments are limited and largely consist of the use of pain-killers and physiotherapy. In some individuals, osteoarthritis progresses to the extent that total joint replacement is required. Currently we are unable to identify those at risk of developing osteoarthritis. We are also unable to treat those at early disease stages. To change this, we must identify the genes, molecules and processes which cause osteoarthritis.

Osteoarthritic joints, most often knees and hips, undergo structural deterioration, characterised by loss of the joint cartilage which covers the bone ends and normally allows pain-free joint movement. In joint cartilage, the resident cell type - the chondrocyte - needs to maintain a very stable, 'permanent' state so as to preserve and protect this tissue throughout life.
This is in stark contrast to the other main type of cartilage in the body (the growth cartilage), which is responsible for all bone growth and which strangely has almost opposite characteristics to the joint cartilage. In the growth cartilage, the chondrocytes are able to easily transition between different states to enable bone growth and therefore only ever have a 'temporary' state.

I have previously shown that in osteoarthritis, the 'permanent' chondrocytes of the joint cartilage undergo a switch to a 'temporary' state, much like that seen in the growth cartilage. This project will examine why the switching between the two distinct types of chondrocytes ('permanent' vs. 'temporary') in the joint cartilage produces an unstable tissue prone to deterioration and osteoarthritis. It will also look to examine whether we can predict those at risk of osteoarthritis from any abnormalities in their growth cartilage. Together, this research will identify clear targets which could then in the future be investigated for patient benefit. This is vital if we are to reduce the economic and social impact of this disease.

Osteoarthritis (OA), characterised by articular cartilage loss and pathological ossification, affects almost 9 million people in the UK and is a major financial, social and healthcare burden. If we improve our understanding of the mechanisms underpinning disease aetiology this will enable us to deliver new paradigms to identify those at risk of OA, and to deliver personalised interventions to treat patients with OA.

My previous research has shown that in a murine model of ageing-related OA, the articular cartilage chondrocytes undergo a transition from their inherently stable phenotype to a transient one, characteristic of the chondrocytes in the growth plate. Moreover, I revealed an association between growth abnormalities and OA development. This project will build upon this, to translate these pilot data to the human condition, and to examine the hypothesis that:

Retaining a stable articular cartilage phenotype protects against OA

RESEARCH PLAN
By merging my expertise in endochondral bone growth and OA, this NIRG will deliver data describing whether abnormal growth dynamics can predict OA onset, and whether their stabilisation can protect against disease development. Importantly, the proposed studies will assess translation efficacy in terms of human health at all stages.

To deliver this, I will answer:

1) Do altered growth dynamics underpin OA predisposition?
2) Can a switch to a transient chondrocyte phenotype contribute to OA?
3) Does targeted stabilisation of the chondrocyte phenotype protect against OA?

Together, this will permit us to identify at risk individuals, and consider therapeutic approaches based on mechanistic understanding. This will likely lead to long-term patient benefit and societal impact, essential to reduce the burden of this globally relevant disease.

The advances made in this project will impact upon, and benefit, research disciplines spanning basic developmental biology, ageing-related diseases and medical research. Medical communities, and individuals will all benefit from the new knowledge generated.

There is an unmet need for improving our understanding of the mechanisms underpinning joint deterioration in the ageing population and this proposal is shaped by the potential impact of this. This research will not only extend our knowledge of osteoarthritis aetiopathogenesis, but will also identify individuals at risk of osteoarthritis development, as well as new targets for therapeutic investigation. It will therefore likely lead to long-term patient benefit and societal impact from a contribution to global economic activity. The clinical benefits are likely still distant but they are potentially huge and are currently only set to rise in the ageing population. The proposed studies will as such have broad translational potential, and will impact upon the following groups:

ACADEMICS
Academics working in many fields across biology, epidemiology, ageing and imaging research will benefit, as outlined in the 'Academic Beneficiaries' section of this proposal. In particular, staff working on this project will directly impact from this work by gaining and developing research and professional transferable skills through mentorship and the Edinburgh Napier University Research and Innovation Office.

SOCIETY
New disease treatments and improved clinical practice will greatly benefit the general public. Musculoskeletal conditions account for 42% of all reported cases of work related ill health and 30.5% of all years lived with disability. They are therefore an enormous socio-economic burden. Identification of effective new targets for osteoarthritis treatment would therefore hugely benefit both the UK economy and the health of the wider public to enhance quality of life. This work will also be of direct benefit to charities working towards understanding osteoarthritis and joint disease such as Arthritis Research UK. The public engagement activities detailed in the 'Pathways to Impact' will also build on my existing public engagement skills and resources to increase public awareness of my research, which ties in with current concerns with our ageing population.

INDUSTRY
Although the proposed work will yield fundamental knowledge of important questions surrounding joint biology, this information is distant from commercial exploitation. Nevertheless these results could allow in the future for the development of new treatments for osteoarthritis and degenerative joint conditions. The proposed work is therefore applicable to industrial partners as disease-modifying treatments are currently absent and all medications for joint conditions are palliative.

POLICY MAKERS AND GOVERNMENT AGENCIES
The private worldwide healthcare systems and the NHS, as well as equivalent bodies, agencies and organisations overseas will benefit from insight to potential benefits to skeletal health revealed by my proposed research. Similarly, due to the known similarities between human and animal osteoarthritis (e.g. canine hip dysplasia), this work will be of benefit to the Animal Health Trust, NERC, EPSRC and DEFRA.