title: Paget's disease of bone: evidence for complex pathogenetic interactions.
abstract: OBJECTIVE
  Paget's disease of bone (PDB), with a prevalence of 2 to 5% in Caucasians >55 years, is the second most frequent metabolic bone disease, after osteoporosis. PDB characteristics are bone lesions with an imbalanced bone remodeling, resulting in disorganized and nonfully fledged new bone. PDB etiology is not completely understood. In this review, current views on the etiology, clinical aspects, and PDB treatment are summarized and discussed.
  
  
  METHODS
  The PubMed database was searched using the keywords PDB, sequestosome1 (SQSTM1), valosin-containing protein (VCP), receptor activator of nuclear factor-κB (RANK), osteoprotegerin (OPG), RANK ligand (RANKL), mutation, genetic variants, virus, osteosarcoma, bisphosphonates, and denosumab.
  
  
  RESULTS
  Environmental evidence (e.g. viruses) and also genetic risk factors have been found for PDB. Until now, SQSTM1 was the only PDB-causing gene identified. However, PDB patients without SQSTM1 mutations seem to have susceptibility genetic polymorphisms in regions containing the CaSR, ESR1, TNFRSF11B (OPG), TNFRSF11A (RANK), CSF1 (M-CSF), OPTN, TM7SF4 (DC-STAMP), VCP, NUP205, RIN3, PML, and GOLGA6A genes, resulting in an increased risk of developing PDB. The nature of these genes indicates that the regulation of osteoclastogenesis is a key process in PDB pathogenesis. Furthermore, with the involvement of SQSTM1 and VCP in autophagy and in forming protein aggregates, this might also indicate that a disturbance of these processes might be a risk factor.
  
  
  CONCLUSIONS
  Unraveling the PDB genetic background is instrumental to understanding the PDB pathogenesis and the role of slow viruses. Furthermore, it might make early detection and subsequently treatment of risk individuals possible.
authors.affiliation: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors.forename: Pui Yan Jenny
authors.initials: PY
authors.lastname: Chung
authors.forename: Wim
authors.initials: W
authors.lastname: Van Hul
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000251:Adenosine Triphosphatases / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D009154:Mutation; D010001:Osteitis Deformans / Q000235:genetics / Q000473:pathology / Q000628:therapy; D020641:Polymorphism, Single Nucleotide; D039781:PubMed; D000071456:Sequestosome-1 Protein; D000074405:Valosin Containing Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D005819:Genetic Markers; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein