Characterisation and therapeutic intervention of two novel mouse models of Paget's disease of bone

Paget?s disease (PDB) is a common bone disease that affects about 3% of people over the age of 55 in the UK which causes pain, softening of the bones, deafness and arthritis. Genetic factors are important in the disease and two abnormal genes have been discovered. It is unclear how these faulty genes cause PDB and it is also unclear if treatment might be able to protect against disease complications if given early enough. The aim of this project is to develop an experimental model for PDB in order to find out more about why the disease occurs and to determine if early treatment might be effective in preventing complications. If our experiments are successful the information gained from these studies will be used to help design clinical trials of preventative therapy in patients with the faulty genes.

Paget‘s disease of bone (PDB) is a common disorder that affects up to 3.1% of individuals over the age of 55 in the UK. Paget‘s disease seriously impacts on quality of life by causing bone pain, deformity, deafness, osteoarthritis and pathological fractures. Genetic factors are important in PDB. Mutations in the TNFRSF11A gene which encodes RANK cause a severe early onset type of PDB and related syndromes of familial expansile osteolysis and expansile skeletal hyperphosphatasia. Mutations in the SQSTM1 gene which encodes p62, a scaffold protein in the NFkB pathway, have been found to be an important cause of classical PDB accounting for up to 40% of familial and 11% of sporadic cases. Antiresorptive drugs have been widely used in the treatment of PDB and are effective at suppressing metabolic activity. However, these drugs have a limited impact on complications and morbidity, probably because the disease is usually far advanced by the time treatment is commenced. In view of this, there is a need to develop a disease model for PDB with which to explore the effects of early intervention to determine if this might be effective in preventing lesion development, since patients at risk of PDB with the above mutations can now be identified by genetic testing. We have recently developed two mouse models of PDB which carry a truncating mutation in SQSTM1 and a duplication mutation in TNFRSF11A. Preliminary analysis showed that these mice develop focal osteolytic lesions characteristic of PDB. Therefore, the mutant mice may represent the first animal models of PDB. The aim of this project is to use these animal models to investigate the cellular and molecular mechanisms by which these mutations affect bone cell function to cause osteolytic lesions. We will also study the possible role of environmental factors on disease development focusing on dietary calcium deficiency which has been implicated in disease severity in humans. Finally we will determine if prophylactic intervention with antiresorptive drugs can prevent the development of osteolytic lesions in these mice. The study will increase our understanding of the molecular pathways involved in the pathogenesis of PDB and provide an invaluable tool to determine disease progression and therapeutic responses.