Dr Asim Azfer, from the University of Edinburgh, summarises below new genetic research into Paget’s disease, which has been funded by the Paget’s Association.

Genetic Factors of Paget’s Disease

Genetic factors are important in Paget’s disease, but the mechanisms by which genetic variations cause the disease are not fully understood. Previous studies have pinpointed a region on human chromosome 1p13, which is strongly associated with Paget’s disease. This is interesting since the same region contains a gene called CSF1, which codes for a cytokine called Macrophage Colony Stimulating Factor (M-CSF). This is relevant to Paget’s, as M-CSF plays a key role in the development of bone-resorbing cells (osteoclasts). We believe that the genetic variants that predispose to Paget’s disease in this region, might do so by causing increased production of M-CSF, which in turn would be expected to stimulate osteoclast activity and bone resorption, and therefore act as a causal factor for the condition.

The aim of this study is to determine whether the gene variants that are associated with Paget’s disease, are also associated with increased circulating M-CSF levels, and to investigate whether levels of M-CSF are associated with signs or symptoms in people with the disease.

This research will result in improved understanding of what causes Paget’s. We already know that variations in a gene called SQSTM1 predisposes to the disease by increasing activity of osteoclasts, and there is evidence that the same applies for other genes including OPTN and PML. The mechanisms by which other genes predispose to Paget’s disease are unknown.

This study will clarify if genetically mediated elevations in levels of M-CSF (produced by the CSF1 gene) are a risk factor for Paget’s and if levels of M-CSF are associated with signs or symptoms of Paget’s disease. If this theory is correct, it could be relevant clinically, in opening up new avenues for treatment, since monoclonal antibodies and small molecule inhibitors of the receptor for M-CSF, which have already been developed for the treatment of autoimmune cancer, could be repurposed for the treatment of Paget’s disease.

Sept 2020

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