Dr Anna Daroszewska, from the University of Liverpool, explains below, new research, funded by the Paget’s Association.

Understanding Excessive Bone Formation in Paget’s Disease

Paget’s Disease of Bone is characterised by focally increased bone remodelling, which is driven by hyperactive bone-dissolving cells, known as osteoclasts. These hyperactive pagetic osteoclasts ‘hijack’ bone-making cells, known as osteoblasts, and force them to produce an excessive amount of bone, which can lead to deformity and pain. Rarely, this excessive bone formation may get out of control and the pagetic bone undergoes transformation into bone cancer (osteosarcoma), which is very difficult to treat, as we do not understand the underlying mechanism causing it.

It is well established that one of the most common genetic causes of Paget’s disease is a mutation in a gene called Sequestosome 1. This is responsible for making a molecule known as p62, which has many important functions within cells. P62 is a scaffolding molecule, which connects other molecules in communication channels (known as signalling pathways) and plays a role in waste disposal and cell ‘cleansing’. The abnormal pagetic p62 causes a sustained increase in signalling in pagetic osteoclasts, hence development of pagetic lesions. On the other hand, p62 is important in cancer cells, although its role is incompletely understood., Reducing the activity of p62, however, has been shown to improve the outcome in some cancers and in theory could be of benefit in Paget’s disease, or other conditions of the ageing skeleton, characterised by high osteoclast activity, such as osteoporosis.

To study whether removing p62 would be beneficial in age-related bone loss, i.e. osteoporosis, in a collaborative project with an Italian group, we set out to analyse the bones in a pre-clinical model lacking p62, however, unexpectedly, found evidence of exacerbated new bone formation, which could be detrimental in Paget’s disease.

In this new research project, funded by the Paget’s Association, we will study in detail the changes in bone cells and tissues, which appear in the absence of p62, so that we gain an understanding of the underlying mechanism driving the excessive bone formation and determine whether it could lead to osteosarcoma. This knowledge is important, as we need to understand the consequences of dampening the activity of p62 in Paget’s disease, should such treatment be offered for another reason (such as adjunctive treatment to chemotherapy for prostate or breast cancer) to individuals affected by Paget’s disease, or carriers of a pagetic mutation.

Sept 2020


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