Ageing and the progression to disease and frailty
Theme 2 aims to identify the processes driving the progression of musculoskeletal decline with age towards clinical frailty, rheumatoid arthritis and osteoarthritis. This theme will also identify drivers of musculoskeletal decline in diseases where sarcopenia and weakness prevail (Chronic Obstructive Pulmonary Disease, inflammatory bowel disease, trauma/infection).
Professor Greenhaff has a longstanding interest in COPD-associated sarcopenia through his involvement in the Medical Research Council/ABPI Chronic Obstructive Pulmonary Disease consortium and Professor Buckley is a theme lead in the Versus Arthritis Rheumatoid Arthritis Pathogenesis Centre of Excellence, which ensures good links to the MRC Versus Arthritis Centre for Musculoskeletal Ageing Research.
The theme integrates Principal Investigators researching various aspects of musculoskeletal disease pathogenesis. This includes how the
microbiome influences systemic inflammation and disease pathogenesis. The human intestine contains a diverse array of bacteria that contribute to health but when dysregulated can also promote disease. Recent studies in inflammatory arthritis suggest alterations in the intestinal microbiota and its interaction with the immune system may underlie disease. However, whether these changes are causal or correlative and their mechanism of action remain to be established.
- Dr Simon Wyn Jones investigates epigenetic mechanisms in pathogenesis, studying the role of long non-coding RNAs in driving the increased risk of osteoarthritis with obesity and assessing their potential as therapeutic targets;
- Tissue resident stromal cells play a role in determining the switch to persistence in rheumatoid arthritis and Professor Buckley researches how ageing processes in fibroblasts affect this switch and offer a new therapeutic target;
- Dr Rowan Hardy investigates the interaction between inflammation and glucocorticoid metabolism (11βHSD1 activity) as a driver of muscle and bone degradation with ageing and in rheumatoid arthritis, working with very early arthritis samples as well as animal models of rheumatoid arthritis on an 11βHSD1-/- background;
- Professors Atherton and Greenhaff (with Professor Dileep Lobo, Versus Arthritis Pain Centre, and Versus Arthritis Centre for Sport, Exercise and Osteoarthritis, and Professor Mick Steiner, Leicester Respiratory Biomedical Research Centre theme) are determining the contribution of physical inactivity to muscle dysfunction in osteoarthritis and COPD, and the mechanistic basis of trauma and infection-related sarcopenia and metabolic dysregulation;
- Dr Liz Sapey works on the role of innate immunity and systemic inflammation in muscle wasting in COPD;
- Professor Janet Lord researches the processes driving sarcopenia in rheumatoid arthritis, chronic liver disease and inflammatory bowel disease using his extensive clinical cohorts and using support from the Birmingham Inflammation Biomedical Research Centre;
- Professor Andy Clark is assessing dysregulation of anti-inflammatory mechanisms in ageing and rheumatoid arthritis pathogenesis, looking at the regulation of the master inflammatory gene regulator tristetraprolin by DUSP phosphatases;
- Dr Helen McGettrick is assessing a novel anti-inflammatory adipokine signalling mechanism.
This theme is led by
Professor Paul Greenhaff
(University of Nottingham)
and Professor Chris Buckley
(University of Birmingham)