Paget's Disease

Introduction

Research on the pathogenesis and management of Paget's disease of bone is led by Professor Stuart H Ralston. Genetic factors play an important role in the pathogenesis of Paget's disease and mutations in four genes have now been identified that cause Paget's disease and related syndromes (reviewed by Daroszweska & Ralston Clin Sci 2005). The first gene to be identified as a cause of a Paget's disease-like syndrome was TNFRSF11A which encodes the Receptor Activator of Nuclear Factor Kappa B (RANK). The disease causing mutations cluster in exon 1 and result in failure of normal processing of the RANK signal peptide and NFkB activation (Hughes et al. Nat Gen 2001). It has now become clear that mutations of TNFRSF11A are responsible for the clinically related syndromes of Familial Expansile Osteolysis, Expansile Skeletal Hyperphosphatasia and early onset familial Paget's disease (Nakatsuka et al. J Bone Miner Res 2004), but do not contribute to classical late-onset Paget's disease.

Mutations in the TNFRSF11B gene which encodes the Osteoprotegerin protein cause the syndrome of Juvenile Paget's disease which is a rare recessively inherited form of Paget's disease. Several disease causing mutations have been described and all result in loss of OPG function (Chong et al, J Bone Miner Res 2004). There is evidence that polymorphisms of TNFRSF11B also regulate susceptibility to classical Paget's disease (Daroszewska et al. J Bone Miner Res 2004).

The rare syndrome of inclusion body myopathy, Paget's disease, and fronto-temporal dementia (IBMPFD) is caused by mutations in the VCP gene (Watts et al. Nat Gen 2004). It is of interest that the disease-causing mutations of VCP cluster in and around the cdc48 domain of the molecule which has ubiquitin binding properties. This suggest that disease mechanisms in VCP mediated Paget's disease may be similar to those in SQSTM1 mediated Paget's disease (see below). Mutations of VCP have not been found in Paget's disease patients without myopathy and dementia however and polymorphisms of VCP do not appear to predispose to classical Paget's disease (Lucas et al, Bone 2005).

Several genome wide searches have been performed in Paget's disease. These have shown that Paget's disease is genetically heterogeneous with candidate loci on chromosomes 2q36, 5q35, 5q31 and 10p13 (Laurin et al, Am J Hum genet 2001), (Hocking et al. Am J Hum Genet 2001). Positional cloning studies of the 5q35 locus resulted in the identification of mutations affecting the ubiquitin associated (UBA) domain of the Sequestosome 1 (SQSTM1) gene as an important cause of Paget's disease (Laurin et al. Am J Hum Genet 2002), (Hocking et al, Hum Mol Gen 2002). Eleven different disease-causing mutations of SQSTM1 have now been identified as a cause of Paget's disease and all of these cluster in the UBA domain. Collaborative studies with Dr Robert Layfield at the University of Nottingham have shown that these are loss of function-mutations which abolish or inhibit ubiquitin binding (Cavey et al. J Bone Miner Res 2005). Research being carried out at present seeks to define the mechanisms by which these mutations affect bone cell function. Whilst SQSTM1 mutations occur in about 40% of people with a family history of Paget's disease, other genes remain to be discovered. Ongoing work supported by a Programme Grant from the Arthritis Research Campaign seeks to identify these genes. We are doing this by performing genetic studies and linkage analysis in families with Paget's disease.

The role of environmental factors in the aetiology of Paget's disease is also being pursued, focusing particularly on the possible role of viruses in aetiology. Previously we have failed to detect evidence of chronic virus infection in bone tissue from patients with Paget's disease (Helfrich et al. J Bone Min Res 2001), but work in this area is still continuing in collaboration with Dr Miep Helfrich at the University of Aberdeen

Although many drugs have been developed for the treatment Paget's disease, doctors still do not know how they should best be used to give the maximum benefit to patients. In order to investigate this, Professor Ralston is leading a large scale clinical trial called the PRISM study which seeks to determine the best way of managing Paget's disease. The PRISM study involves 1331 patients in 42 hospitals in the UK and compares the effects of "intensive" treatment for Paget's disease with drugs that suppress bone turnover, with "symptomatic" treatment which focuses only on the control of symptoms. The PRISM study is jointly funded by the Arthritis Research Campaign and the National Association for Relief of Paget's disease. The first patients were enrolled in 2001 and the results of the study are expected to be available towards the end of 2006.

In addition to informing doctors about the best way of treating Paget's disease, a DNA repository is being set up from participants of the PRISM study to investigate the genetic basis of Paget's disease and it's response to treatment.

	Introduction Projects Publications Biography Contact	Paget's Disease Introduction Research on the pathogenesis and management of Paget's disease of bone is led by Professor Stuart H Ralston. Genetic factors play an important role in the pathogenesis of Paget's disease and mutations in four genes have now been identified that cause Paget's disease and related syndromes (reviewed by Daroszweska & Ralston Clin Sci 2005). The first gene to be identified as a cause of a Paget's disease-like syndrome was TNFRSF11A which encodes the Receptor Activator of Nuclear Factor Kappa B (RANK). The disease causing mutations cluster in exon 1 and result in failure of normal processing of the RANK signal peptide and NFkB activation (Hughes et al. Nat Gen 2001). It has now become clear that mutations of TNFRSF11A are responsible for the clinically related syndromes of Familial Expansile Osteolysis, Expansile Skeletal Hyperphosphatasia and early onset familial Paget's disease (Nakatsuka et al. J Bone Miner Res 2004), but do not contribute to classical late-onset Paget's disease. Mutations in the TNFRSF11B gene which encodes the Osteoprotegerin protein cause the syndrome of Juvenile Paget's disease which is a rare recessively inherited form of Paget's disease. Several disease causing mutations have been described and all result in loss of OPG function (Chong et al, J Bone Miner Res 2004). There is evidence that polymorphisms of TNFRSF11B also regulate susceptibility to classical Paget's disease (Daroszewska et al. J Bone Miner Res 2004). The rare syndrome of inclusion body myopathy, Paget's disease, and fronto-temporal dementia (IBMPFD) is caused by mutations in the VCP gene (Watts et al. Nat Gen 2004). It is of interest that the disease-causing mutations of VCP cluster in and around the cdc48 domain of the molecule which has ubiquitin binding properties. This suggest that disease mechanisms in VCP mediated Paget's disease may be similar to those in SQSTM1 mediated Paget's disease (see below). Mutations of VCP have not been found in Paget's disease patients without myopathy and dementia however and polymorphisms of VCP do not appear to predispose to classical Paget's disease (Lucas et al, Bone 2005). Several genome wide searches have been performed in Paget's disease. These have shown that Paget's disease is genetically heterogeneous with candidate loci on chromosomes 2q36, 5q35, 5q31 and 10p13 (Laurin et al, Am J Hum genet 2001), (Hocking et al. Am J Hum Genet 2001). Positional cloning studies of the 5q35 locus resulted in the identification of mutations affecting the ubiquitin associated (UBA) domain of the Sequestosome 1 (SQSTM1) gene as an important cause of Paget's disease (Laurin et al. Am J Hum Genet 2002), (Hocking et al, Hum Mol Gen 2002). Eleven different disease-causing mutations of SQSTM1 have now been identified as a cause of Paget's disease and all of these cluster in the UBA domain. Collaborative studies with Dr Robert Layfield at the University of Nottingham have shown that these are loss of function-mutations which abolish or inhibit ubiquitin binding (Cavey et al. J Bone Miner Res 2005). Research being carried out at present seeks to define the mechanisms by which these mutations affect bone cell function. Whilst SQSTM1 mutations occur in about 40% of people with a family history of Paget's disease, other genes remain to be discovered. Ongoing work supported by a Programme Grant from the Arthritis Research Campaign seeks to identify these genes. We are doing this by performing genetic studies and linkage analysis in families with Paget's disease. The role of environmental factors in the aetiology of Paget's disease is also being pursued, focusing particularly on the possible role of viruses in aetiology. Previously we have failed to detect evidence of chronic virus infection in bone tissue from patients with Paget's disease (Helfrich et al. J Bone Min Res 2001), but work in this area is still continuing in collaboration with Dr Miep Helfrich at the University of Aberdeen Although many drugs have been developed for the treatment Paget's disease, doctors still do not know how they should best be used to give the maximum benefit to patients. In order to investigate this, Professor Ralston is leading a large scale clinical trial called the PRISM study which seeks to determine the best way of managing Paget's disease. The PRISM study involves 1331 patients in 42 hospitals in the UK and compares the effects of "intensive" treatment for Paget's disease with drugs that suppress bone turnover, with "symptomatic" treatment which focuses only on the control of symptoms. The PRISM study is jointly funded by the Arthritis Research Campaign and the National Association for Relief of Paget's disease. The first patients were enrolled in 2001 and the results of the study are expected to be available towards the end of 2006. In addition to informing doctors about the best way of treating Paget's disease, a DNA repository is being set up from participants of the PRISM study to investigate the genetic basis of Paget's disease and it's response to treatment.
	Updated: Tue, 5th October, 2010