Please can you give a brief introduction to osteoarthritis? What are the main symptoms of the condition and who does it affect?
Osteoarthritis is an extremely common condition affecting about 8 million people in the UK. The elderly are particularly susceptible, with up to 45% of people over 65 years, having the disease.
Osteoarthritis usually affects the knees, hips, hands or spine, causing joint pain, stiffness and loss of mobility. The painful joint becomes deformed and swollen and the cartilage, which covers the ends of the bone, is degraded and roughened.
Osteoarthritis affects many of us, but the risk is increased if you have a physical job, are overweight, have had a previous joint injury, or if you have a family history of the disease.
It is clear that mechanical loading of joints plays an important part in causing osteoarthritis.
Why does osteoarthritis affect more women than men?
Not only does osteoarthritis affect more women than men, but women also tend to get it more severely. The reasons for this are not completely clear but may be due to differences in joint anatomy as well as the effects of oestrogen on the skeleton.
You have recently been awarded a grant of £200,000 to investigate new drugs to treat early onset osteoarthritis. How common is early onset arthritis?
This is a difficult question, as we do not have the means to diagnose osteoarthritis in its early stages.
Early stages of osteoarthritis are usually asymptomatic and patients who consult their GP’s with painful joints usually have advanced disease where the cartilage is already lost.
However, in many of these patients, osteoarthritis may have started years earlier, perhaps because they are overweight or have injured their joint.
For example, of the tens of thousands of patients that suffer a serious knee injury that destabilises the joint in the UK per annum, up to 50% may go on to develop osteoarthritis over the next 15 years.
What drugs are currently available to treat early onset osteoarthritis and why is there a need to develop new drugs?
There are no drugs to treat osteoarthritis, either in early or later stages. The best we can do is to relieve symptoms of pain and inflammation using non-steroidal anti inflammatory drugs (NSAIDs) or pain-killers like paracetamol.
Since patients are usually not diagnosed with osteoarthritis until the disease is advanced and no therapies can restore the cartilage that has already been lost, then joint replacement surgery is the only option if the pain becomes unmanageable.
Recently it has emerged that osteoarthritis involves similar inflammatory signals as other forms of arthritis such as rheumatoid. Rheumatoid arthritis is now effectively treated in many patients using new drugs, which inhibit inflammatory signals and prevent joint destruction.
Therefore, trials are being developed to determine whether such drugs may be effective in controlling inflammation and joint destruction in osteoarthritis.
How do you plan to use the grant from medical research charity Arthritis Research UK?
A molecule called glutamate is released into the joint at very high concentrations in arthritis and can act on receptors in bone, cartilage and synovial cells in the joint, as well as nerves. We, and others, have shown that glutamate signals are mechanically regulated, and can lead to inflammation and pain in specific joint tissues.
This grant will determine whether the glutamate released in arthritis also causes joint destruction and determine whether inhibiting the signal either with specific drugs, or by altering the mechanics of the joint, can prevent any destructive effects of glutamate.
We are particularly interested in whether glutamate drives changes in the bone that may precede joint degeneration in osteoarthritis.
What are the aims of this research?
We know that mechanical loading of bone alters glutamate signals, but do not know how important this is in causing early arthritis. So firstly, we will determine whether mechanical load and high glutamate concentrations cause changes in the bone that lead to joint degeneration.
This will enable us to identify specific glutamate receptors in bone that drive arthritic joint damage at early stages of the disease.
Inhibitors to these receptors will then be tested to determine their potential as future drug targets.
How will this study be building on earlier research?
After our surprising discovery that the neurotransmitter glutamate is mechanically regulated in bone1, we, and others, showed that cells from different musculoskeletal tissues express functional glutamate receptors that influence cell division, inflammation and degeneration2-6.
Others showed that glutamate concentrations increased in the joint fluids of patients with osteoarthritis and rheumatoid arthritis, and that this contributes to arthritic pain7.
We demonstrated that human synoviocytes (joint lining cells) from patients with rheumatoid arthritis respond to these high glutamate concentrations by increasing release of an essential mediator of joint destruction in inflammatory arthritis, called interleukin 63.
We reasoned that blocking the specific glutamate receptor that caused release of IL-6 would protect against inflammatory arthritis and recently showed that such a drug profoundly reduced joint degeneration in inflammatory arthritis in work funded by the Arthritis Research UK Biomechanics and Bioengineering Centre8.
Now we are trying to work out when and how to use these types of drugs to treat early stages of osteoarthritis.
- Mason DJ, Suva LJ, Genever PG, Patton AJ, Steuckle S, Hillam RA, and Skerry TM (1997). Mechanically-regulated expression of a neural glutamate transporter in bone. A role for excitatory amino acids as osteotropic agents? Bone 20 (3):199-20.
- Mason DJ (2004) Glutamate Signalling and its Potential Application to Tissue Engineering of bone. European Cells and Materials 7:12-26.
- Flood S, Parri R, Williams A, Duance V, Mason D. Modulation of interleukin-6 and matrix metalloproteinase 2 expression in human fibroblast-like synoviocytes by functional ionotropic glutamate receptors. Arthritis Rheum. 2007;56:2523-34.
- Piepoli T, Mennuni L, Zerbi S, Lanza M, Rovati LC, Caselli G. Glutamate signaling in chondrocytes and the potential involvement of NMDA receptors in cell proliferation and inflammatory gene expression. Osteoarthritis Cartilage. 2009;17:1076-83.
- McNearney TA, Ma Y, Chen Y, Taglialatela G, Yin H, Zhang WR, et al. A peripheral neuroimmune link: glutamate agonists upregulate NMDA NR1 receptor mRNA and protein, vimentin, TNF-alpha, and RANTES in cultured human synoviocytes. Am J Physiol Regul Integr Comp Physiol. 2010;298:R584-98.
- Brakspear KS, Mason DJ. Glutamate signaling in bone. Front Endocrinol (Lausanne). 2012;3:97.
- McNearney T, Baethge BA, Cao S, Alam R, Lisse JR, Westlund KN. Excitatory amino acids, TNF-alpha, and chemokine levels in synovial fluids of patients with active arthropathies. Clin Exp Immunol. 2004;137:621-7.
- Bonnet CS, Williams AS, Gilbert SJ , Harvey AK, Evans BA , and Mason DJ. AMPA/kainate glutamate receptors contribute to inflammation, degeneration and pain related behaviour in inflammatory stages of arthritis. Annals Rheumatic Diseases (2013): under review.
What hurdles do you expect to face and how do you plan to overcome them?
There are a number of hurdles to this type of research. Firstly, we continually have to ensure that all relevant intellectual property is protected before we disclose our data. This is important to facilitate any future clinical trials in humans, but delays communications and publications.
Scientifically, the main hurdle is to identify which glutamate receptors mediate the most damaging changes, and when is the optimal time to intervene in human disease. This project uses models of human injury-induced osteoarthritis to identify which receptors to target and assess whether early intervention is protective.
Related work in my team in the Arthritis Research UK Biomechanics and Bioengineering Centre in Cardiff, will enable us to relate findings from these laboratory experiments directly to biological and biomechanical changes in human osteoarthritis.
How long do you estimate this research to take?
This project is funded for 3 years and will identify and test some glutamate receptor antagonists in preclinical models.
It will take much longer to test the effectiveness of these drugs in humans, not least because injury-induced osteoarthritis takes 5 to 15 years to develop. However, since many glutamate receptor antagonists already have safety (Phase I) data in man, they represent a great opportunity to quickly develop new treatments.
Do you think that early treatments for osteoarthritis could prevent the need for joint replacement?
If early intervention completely halts disease progression, then the need for joint replacement could be prevented. However, it is more likely that such treatments would slow the development of the disease and therefore significantly delay the necessity for joint replacement surgery. Since these drugs also reduce pain, this could be a secondary benefit, over and above any on joint degeneration.
How do you think the future of osteoarthritis treatments will develop?
Our research has shown that factors that cause joint pain are directly regulated by mechanical loading through the joint and also cause joint swelling and joint destruction. We are trying to understand how loading through joints causes these changes in arthritis.
Our long-term aim is to develop new ‘golden bullet’ drug targets that treat the symptoms (pain and swelling) as well as the problem (joint destruction) in arthritis. However, all of these drugs will only be useful if we can develop assays to screen for early stages of osteoarthritis and also indicate whether a particular treatment is effectively slowing or halting the disease.
There is a worldwide endeavor to develop such assays. To this end in Cardiff, we are combining biological, imaging and functional data to provide much more detail about arthritic changes. This may enable us to develop new biomechanical interventions (surgery, rehabilitation, prostheses) to use alone, or in combination with new drugs, to prevent osteoarthritis.
Where can readers find more information and keep up to date with your research?
About Dr Deborah Mason
After my BSc in Zoology and Genetics (1986) and my PhD in Evolutionary Genetics (1991) in Cardiff, I worked briefly in Medical Genetics at the University Hospital of Wales before moving to Bristol University.
My research in Bristol revealed osteocyte gene expression in vivo and implicated glutamatergic signalling in mechanically-induced bone formation.
Since my appointment as Lecturer in Cardiff University in 1996 (Senior Lecturer in 2009, Reader in 2012), I have investigated the role of glutamate transporters in bone, revealed a pathological role for glutamate in arthritis, and identified new pathways of cytokine- and mechanically- induced cartilage degradation involving PKR, ceramide and the cytoskeleton.
I have secured over £12M of research funding for 30 projects. I co-ordinated Cardiff’s bid for the Arthritis Research UK-funded Centre of Excellence in Biomechanics and Bioengineering, where I act as a manager, and as the Biomechanics, Inflammation and Pain Team Leader.
I have served on the Bone Research Society and the British Orthopaedic Research Committees. I have supervised 11 PhD/MD students and teach undergraduate students, co-ordinating the Molecular Biology Degree Scheme in Cardiff and acting as final year tutor for all Biomolecular Degree Schemes. I regularly contribute to public engagement activities with school children, patients and fundraisers.
About Arthritis Research UK
Arthritis Research UK is the leading authority on arthritis in the UK, conducting scientific and medical research into all types of arthritis and related musculoskeletal conditions. It is the UK’s fourth largest medical research charity and the only charity solely committed to funding high quality research into the cause, treatment and cure of arthritis.
Research explores the health benefits of resistant starch in plant-based diets