TARGETING CELLULAR SENESCENCE TO COMBAT INTERVERTEBRAL DISC DEGENERATION AND OSTEOARTHRITIS

Conflicts of Interest: None Sources of Funding: Funded by Arthritis UK Introduction Intervertebral disc (IVD) degeneration and osteoarthritis are leading causes of disability worldwide, leading to substantial pain, decreased mobility and major impacts on individuals' quality of life. However, current treatments do not target the underlying biological causes. Both diseases share several commonalities. We hypothesise that by targeting a common pathway in the development of osteoarthritis and IVD degeneration known as cellular senescence, where cells no longer divide but continue to produce catabolic factors that drive degeneration, we will be able to halt the progression of both diseases. This study, aimed to test a range of anti-senescence drugs (senolytics) and novel compounds to target and remove the dysfunctional cells within human IVD and knee tissue explant culture models. Methods IVD tissue explants and combined osteochondral and synovium co-cultures were treated for 1w with previously known senolytic drugs: quercetin, o -vanillin or RG-7112, and novel compounds to target senescent cells and their secretory phenotype. Cell viability, secretome analysis, gene and protein expression were utilised to determine the effects of senolytics on tissues. Results The secretion of cytokines, chemokines and senescent factors was reduced in IVD cultures following treatment with all senolytics, whereas secretion in osteochondral and synovium co-cultures was inhibited the greatest by quercetin. Conclusions Treatment with senolytic compounds decreased the production of the SASP within our human ex vivo osteoarthritis and IVD degeneration models. This indicates that these compounds target the senescent cell populations within our relevant human model systems and provide potentially disease-modifying effects.