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

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Molecular Medicine


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.

Technical Summary

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 intetion 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.


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Ralston SH (2011) Genetic determinants of Paget's disease of bone. in Annals of the New York Academy of Sciences

Description European Research Council starting grant
Amount € 1,493,545 (EUR)
Funding ID 311723-GENEPAD 
Organisation European Research Council (ERC) 
Sector Public
Country Belgium
Start 10/2012 
End 09/2017
Description Travel Award/European Calcified Tissue Society
Amount € 500 (EUR)
Organisation European Calcified Tissue Society (ECTS) 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2010 
End 07/2010
Title Mouse Models of Paget's disease of bone 
Description Two mouse models mimicking Paget's disease of bone were generated. The first model was generated by genetic modification of the RANK gene which causes early-onset form of Paget's disease in human. The second model was generated by genetic modification of the SQSTM1 gene which causes classical Paget's disease of bone. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Since PDB is a late-onset disease and evolves over several decades, it is difficult to investigate the natural history of PDB in clinical studies. It is similarly difficult to determine whether or not early intervention with disease modifying therapy might favourably influence the course of the disease. Therefore, PDB is an ideal candidate to be investigated in animal models. In view of this, we have developed these two models for severe PDB to investigate disease mechanism and study if early therapeutic interventions prevent progression of the disease. 
Description Analysis of bone lesions using electron microscopy 
Organisation University of Aberdeen
Department Institute of Medical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Our contribution was to provide bone samples from our Paget's disease models for analysis using electron microscopy.
Collaborator Contribution The collaborators will contribut to the analysis of osteolytic bone lesions using electron microscopy.
Impact The work is still in near completion and output is being prepared for submission for publication.
Start Year 2010
Description Presentation at the Spanish Society for Bone and Mineral Research (SEIOMM) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact 500 participants attended which stimulated discussions and questions afterwards.

Year(s) Of Engagement Activity 2010