New avenues for intervention in age-related degenerative disease in the horse: unravelling the role of altered RNA splicing and senescence in tendon

Approximately 1 in 4 people in the UK are affected by musculoskeletal conditions, which have a huge impact on quality of life. As large mammals, horses are also prone to musculoskeletal conditions, and injuries. This University of Brighton project looks at treating musculoskeletal disease, focussing on tendons because the horse provides a highly relevant, naturally occurring, animal model of human tendon disease.
Naturally occurring tendon cells have a tendency to 'age', one of the main ways by which humans become more prone to diseases as they grow older.

Once these natural cells 'age', they are more likely to be removed by the immune system but those remaining produce chemicals which contribute to further damage to tissues. This cell 'ageing' is made worse by corticosteroids, which are often used as treatment for joint and tendon disease in humans.

Researchers will be using resveratrol (RSV), a naturally-occurring nutritional supplement, which has been shown to reverse ageing effects in cells, increasing their ability to divide and grow. We have created a panel of different types of RSV which can inhibit some of the specific pathways of ageing and so can be used in experiments to help determine the role of corticosteroids in their behaviour and how RSV may provide protection. This unique collaboration between scientists and veterinary clinicians will be undertaking lab-based work using tendons and cells taken from the animal models, which will allow us to understand how to improve treatment in horses, and ultimately humans.

Superficial digital flexor tendinopathy is a major cause of morbidity and mortality in equine athletes. It is preceded by age-related molecular changes indicating a failure of effective adaptive remodelling together with the accumulation of degraded matrix and is followed by dysfunctional healing with a high risk of re-injury. Clearly, the ability to postpone or prevent the initial process of degeneration and/or enhance repair post-injury would provide an effective strategy for both prevention and treatment of this common condition.

Previous studies have revealed increased cytokine and matrix metalloproteinase expression, a hallmark of the senescence associated secretory phenotype (SASP) of senescent cells. In addition, RNA splicing has recently been shown to be integral to a cell response to stress and both of these mechanisms have been recently strongly implicated in ageing and age-related degenerative diseases, of which equine tendinopathy is a good example. This unique collaboration provides the tools to investigate the relative importance of each of these mechanisms and, in particular, have developed unique that can induce or inhibit each of these pathways. By evaluating this in tendon explants subjected to relevant stresses in vitro, we can identify novel candidate molecules that slow or stop the degenerative process, which, because they are small molecules, could be delivered transdermally in a subsequent study on live horses.