Targeting autophagy in Paget's disease

The Michael Davie Student Research Bursary

Thanks to funding from the Michael Davie Research Foundation, the Paget’s Association was able to provide a Student Research Bursary Award of £6,000 to Jack Beard. This funded research into the treatment of Paget’s disease, ‘Targeting Autophagy in Paget’s Disease’ and took place at the University of Oxford. The project is summarised below. [2017-2018]

Exploring autophagy in relation to Paget’s

It is unsurprising that the accumulation of rubbish leads to all sorts of problems! Interestingly, the cellular environment is not so dissimilar to our city streets, where unwanted or defective products litter the pathways and obstruct normal behaviour. This is certainly true in Paget’s Disease of Bone, where the accumulation of debris within critical cells of bone creates a trash-filled blockage, which impairs their ability to function adequately.

Thanks to the Michael Davie Student Research Bursary, researchers at the University of Oxford have been exploring how changes in waste disposal within the cells of bone might be associated with the development of Paget’s disease and importantly, whether treatment with bisphosphonate drugs might improve the removal and recycling process (autophagy) to restore normal bone cell biology. Paget’s Disease of Bone is primarily driven by defects in bone-resorbing osteoclasts (see page 9 for a detailed explanation of how bone cells function). The dysregulated removal of bone leads to weakened long bone structure, which adopts a characteristic bowed appearance, as is visible on x-ray. In most cases, Paget’s disease can be successfully treated with bisphosphonates, which effectively kill the osteoclasts, reducing the aberrant bone destruction and restoring the delicate cellular balance within the skeleton. In recent years, large scale genomic studies of patients with Paget’s disease have been successful in identifying a small selection of target genes, whose altered function is associated with the development of the disease, and which includes ‘Sequestosome 1’ protein. Interestingly, this gene product helps to regulate the cellular waste removal process of autophagy – necessary for optimal cellular health and ageing.

The work conducted as a result of the Student Bursary Award has revealed a previously unknown mechanism of action of bisphosphonates, in that they might also have the potential to stimulate autophagy. Human cells treated in culture with a panel of bisphosphonate drugs known to possess a diverse range of potencies and activity, showed an increased stimulation of autophagy-related proteins. This finding raises the possibility that treatment with bisphosphonates might also improve Paget’s Disease of Bone by stimulating a more effective removal of waste products within the cells of bone. Interestingly, this work also suggests that bisphosphonates might impact a healthy lifespan through the stimulation of this pro-ageing mechanism. The team in Oxford, who have worked alongside Jack, report that further study is necessary to progress this research further.