Pathogenesis of Paget Disease of Bone

Stuart H. Ralston*, Rob Layfield

*Corresponding author for this work

Research output: Contribution to journalLiterature reviewpeer-review

Abstract

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 SQSTM1, which harbors mutations that cause osteoclast activation in 5-20 % of PDB patients. Seven additional susceptibility loci for PDB have been identified by genomewide association studies on chromosomes 1p13, 7q33, 8q22, 10p13, 14q32, 15q24, and 18q21. Although the causal variants remain to be discovered, three of these loci contain CSF1, TNFRSF11A, and TM7SF4, genes that are known to play a critical role in osteoclast differentiation and function. Environmental factors are also important in the pathogenesis of PDB, as reflected by the fact that in many countries the disease has become less common and less severe over recent years. The most widely studied environmental trigger is paramyxovirus infection, but attempts to detect viral transcripts in tissues from patients with PDB have yielded mixed results. Although our understanding of the pathophysiology of PDB has advanced tremendously over the past 10 years, many questions remain unanswered, such as the mechanisms responsible for the focal nature of the disease and the recent changes in prevalence and severity.

Original languageEnglish
Pages (from-to)97-113
Number of pages17
JournalCalcified Tissue International
Volume91
Issue number2
DOIs
Publication statusPublished - Aug 2012

Keywords

  • GENOME-WIDE ASSOCIATION
  • FAMILIAL EXPANSILE OSTEOLYSIS
  • VALOSIN-CONTAINING PROTEIN
  • RETICULUM-ASSOCIATED DEGRADATION
  • Osteoclast
  • Cartilage
  • Paget disease of bone
  • RESPIRATORY SYNCYTIAL VIRUS
  • UBIQUITIN-ASSOCIATED DOMAIN
  • NF-KAPPA-B
  • COLONY-STIMULATING FACTOR
  • CANINE-DISTEMPER VIRUS
  • POLYMERASE CHAIN-REACTION

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