Pathogenesis of Paget Disease of Bone

@article{Ralston2012PathogenesisOP,
  title={Pathogenesis of Paget Disease of Bone},
  author={Stuart H. Ralston and Robert Layfield},
  journal={Calcified Tissue International},
  year={2012},
  volume={91},
  pages={97-113}
}
Paget disease of bone (PDB) is a common disease characterized by focal areas of increased and disorganized bone turnover. Some patients are asymptomatic, whereas others develop complications such as pain, osteoarthritis, fracture, deformity, deafness, and nerve compression syndromes. PDB is primarily caused by dysregulation of osteoclast differentiation and function, and there is increasing evidence that this is due, in part, to genetic factors. One of the most important predisposing genes is… Expand
Paget’s Disease
TLDR
Bisphosphonates are highly effective in suppressing the elevated bone turnover, which is characteristic of PDB, and can help alleviate bone pain, but they are of limited benefit in patients with established disease who have already developed complications. Expand
Genetics of Paget’s Disease of Bone
TLDR
Improved understanding of bone biology and the causes of Paget’s disease raises the prospect that genetic profiling could identify patients at high risk of developing complications, permitting enhanced surveillance and early therapeutic intervention. Expand
Paget’s Disease of Bone
TLDR
The focal nature of lesions, the decline in prevalence rates, and the incomplete penetrance of the disease among family members suggest that one or more environmental triggers may play a role in the pathophysiology of PDB. Expand
Molecular Genetics of Paget's Disease of Bone
TLDR
The genetic architecture of PDB is incompletely understood, but recent evidence suggests that the disease may be caused by a combination of rare variants in genes such as SQSTM1 and more common variants (i.e. polymorphisms) in genessuch as CSF1, TNFRSF11A, OPTN and TM7SF4. Expand
Chapter 25 – Genetics of Paget’s Disease of Bone
TLDR
Advances in PDB genetics have improved understanding of the mechanisms by which bone remodeling is regulated and have uncovered genetic markers of disease occurrence and severity that might be of clinical value. Expand
Paget’s disease of bone: epidemiology, pathogenesis and pharmacotherapy
TLDR
This work has shown that mutations in SQSTM1 gene (encoding p62) have been identified in a consistent proportion of familial cases and treatment opportunities have been recently improved with the use of intravenous aminobisphosphonate regimens, allowing long-term remission of the disease. Expand
Paget’s disease of bone: an update on epidemiology, pathogenesis and pharmacotherapy
TLDR
It is now clear that PDB is a genetically heterogeneous disorder, with at least three different genes involved in the classic form and four additional genes identified in PDB-related syndromes. Expand
VAV3 Gene Polymorphism Is Associated with Paget's Disease of Bone.
TLDR
It is suggested that inheriting the VAV3 rs7528153 polymorphism is a likely susceptibility factor for developing Paget's disease of bone. Expand
SQSTM1 mutations--bridging Paget disease of bone and ALS/FTLD.
TLDR
How knowledge of the impact of PDB-associated SQSTM1 mutations on various cellular processes including NF-κB signaling and autophagy pathways, as well as the locations of the mutations within the p62 primary sequence, may provide new insights into ALS/FTLD disease mechanisms is considered. Expand
Pathobiology of Paget's Disease of Bone
TLDR
The mechanisms responsible for the effects of mutant p62 gene expression and MVNP on osteoclast and osteoblast activity are reviewed, and how they may contribute to the development of Paget's disease of bone is reviewed. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 169 REFERENCES
Pathogenesis of Paget's disease of bone.
TLDR
Genetic factors play an important role in PDB and mutations or polymorphisms have been identified in four genes that cause classical Paget's disease and related syndromes and it is likely that the mutations predispose to PDB by disrupting normal signalling, leading to osteoclast activation. Expand
Mutations of SQSTM1 are associated with severity and clinical outcome in paget disease of bone
  • M. Visconti, A. Langston, +4 authors S. Ralston
  • Medicine
  • Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
  • 2010
TLDR
It is demonstrated that SQSTM1 mutations are strongly associated with disease severity and complications of PDB and a program of genetic testing and early intervention in these individuals would be cost‐effective or be of benefit in preventing these complications. Expand
Recent advances in understanding the molecular basis of Paget disease of bone
TLDR
A review of recent advances in the understanding of the molecular basis of PDB with particular emphasis on findings since 2008, and focus on newly defined functions of the p62 protein upon which SQSTM1 mutations may impact in the development of the pagetic phenotype. Expand
Evaluation of the role of RANK and OPG genes in Paget's disease of bone.
TLDR
The data suggest that RANK is not directly involved in PDB in a set of patients, as no mutations in the RANK coding region could be identified and allele frequencies of RANK polymorphisms did not differ in P DB patients as compared with the random population. Expand
Evaluation of the role of Valosin-containing protein in the pathogenesis of familial and sporadic Paget's disease of bone.
TLDR
Genetic variation in Valosin-containing Protein (VCP) does not appear to be a common cause of familial or sporadic PDB in the absence of myopathy and dementia. Expand
Mutation Screening of the TNFRSF11A Gene Encoding Receptor Activator of NFkB (RANK) in Familial and Sporadic Paget's Disease of Bone and Osteosarcoma
TLDR
Mutation screening of the TNFRSF11A gene in patients with familial and sporadic Paget's disease as well as DNA extracted from Pagetic bone lesions, an osteosarcoma arising in PageticBone and six osteosARcoma cell lines indicate that TNFRL11A mutations contribute neither to the vast majority of cases of sporadic or familial PDB, nor to the development of osteosArcoma. Expand
A SQSTM1/p62 mutation linked to Paget's disease increases the osteoclastogenic potential of the bone microenvironment.
TLDR
Results indicate that this PDB-associated p62 mutation is not sufficient to induce PDB and suggest that additional factors acting together with p 62 mutation are necessary for the development of PDB in vivo. Expand
Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis
TLDR
Two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone caused an increase in RANK-mediated nuclear factor-κB signalling in vitro, consistent with the presence of an activating mutation. Expand
Genomewide search in familial Paget disease of bone shows evidence of genetic heterogeneity with candidate loci on chromosomes 2q36, 10p13, and 5q35.
TLDR
A genomewide search in 319 individuals with familial PDB indicated the presence of several susceptibility loci for PDB and identified a strong candidate locus for the disease, on chromosome 5q35. Expand
Paget disease of bone: mapping of two loci at 5q35-qter and 5q31.
TLDR
The mapping of two novel loci for Paget disease of bone are demonstrated and proposed, providing further evidence for genetic heterogeneity of this highly prevalent disorder. Expand
...
1
2
3
4
5
...