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Mechanisms of Disease: genetics of Paget's disease of bone and related disorders

Nature Clinical Practice Rheumatology volume 2, pages 270–277 (2006)Cite this article

Abstract

Paget's disease of bone (PDB) is a common disorder in which focal abnormalities of increased bone turnover lead to complications such as bone pain, deformity, pathological fractures, and deafness. PDB has a strong genetic component and several susceptibility loci for the disease have been identified by genome-wide scans. Mutations that predispose individuals to PDB and related disorders have been identified in four genes. The rare PDB-like syndromes of familial expansile osteolysis, early-onset familial PDB, and expansile skeletal hyperphosphatasia are caused by insertion mutations in TNFRSF11A, which encodes receptor activator of nuclear factor (NF)κB (RANK)—a critical regulator of osteoclast function. Inactivating mutations in TNFRSF11B, which encodes osteoprotegerin (a decoy receptor for RANK ligand) cause idiopathic hyperphosphatasia, and polymorphisms in this gene seem to increase the risk for classical PDB. Mutations of the sequestosome 1 gene (SQSTM1), which encodes an important scaffold protein in the NFκB pathway, are a common cause of classical PDB. The rare syndrome of hereditary inclusion body myopathy, PDB, and fronto-temporal dementia is caused by mutations in the valosin-containing protein (VCP) gene. This gene encodes VCP, which has a role in targeting the inhibitor of NFκB for degradation by the proteasome. Several additional genes for PDB remain to be discovered, and it seems likely that they will also involve the RANK−NFκB signaling pathway or components of the proteasomal processing of this pathway, underscoring the critical importance of this signaling pathway in bone metabolism and bone disease.

Key Points

  • Paget's disease of bone (PDB) has a strong genetic component and is often inherited as a simple autosomal dominant trait

  • Mutations in four genes have been described that cause PDB or related disorders, and all are involved in the receptor activator of nuclear factor κB signaling pathway

  • Classical PDB is commonly caused by mutations in the gene encoding sequestosome 1 (SQSTM1); these mutations cause the sequestosome 1 protein (p62) to lose its ability to bind ubiquitin

  • Several other genes responsible for PDB remain to be discovered and it seems likely that mutations in these genes will also affect the receptor activator of nuclear factor κB signaling pathway

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Figure 1: Mutations in components of the receptor activator of nuclear factor (NF)κB (RANK)–NFκB signaling pathway cause Paget's disease of bone and related disorders.

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References

  1. Meunier PJ et al. (1980) Bone histomorphometry in Paget's disease. Quantitative and dynamic analysis of pagetic and nonpagetic bone tissue. Arthritis Rheum 23: 1095–1103

    Article  CAS  PubMed  Google Scholar 

  2. Friedrichs WE et al. (2002) The pro and con of measles virus in Paget's disease: pro. J Bone Miner Res 17: 2293

    Article  Google Scholar 

  3. Rima BK (2002) The pro and con of measles virus in Paget's disease: con. J Bone Miner Res 17: 2290–2292

    Article  PubMed  Google Scholar 

  4. Cooper C et al. (1999) The epidemiology of Paget's disease in Britain: is the prevalence decreasing? J Bone Miner Res 14: 192–197

    Article  CAS  PubMed  Google Scholar 

  5. Altman RD et al. (2000) Prevalence of pelvic Paget's disease of bone in the United States. J Bone Miner Res 15: 461–465

    Article  CAS  PubMed  Google Scholar 

  6. van Staa TP et al. (2002) Incidence and natural history of Paget's disease of bone in England and Wales. J Bone Miner Res 17: 465–471

    Article  CAS  PubMed  Google Scholar 

  7. Rogers J et al. (2002) Paget's disease in an archeological population. J Bone Miner Res 17: 1127–1134

    Article  CAS  PubMed  Google Scholar 

  8. Cundy HR et al. (2004) Paget's disease of bone in New Zealand: continued decline in disease severity. Calcif Tissue Int 75: 358–364

    Article  CAS  PubMed  Google Scholar 

  9. Tiegs RD et al. (2000) Long-term trends in the incidence of Paget's disease of bone. Bone 27: 423–427

    Article  CAS  PubMed  Google Scholar 

  10. Gennari L et al. (2005) Prevalence of Paget's disease of bone in Italy. J Bone Miner Res 20: 1845–1850

    Article  PubMed  Google Scholar 

  11. Siris ES (1994) Epidemiological aspects of Paget's disease: family history and relationship to other medical conditions. Semin Arthritis Rheum 23: 222–225

    Article  CAS  PubMed  Google Scholar 

  12. Solomon LR (1979) Billiard-player's fingers: an unusual case of Paget's disease of bone. Br Med J 1: 931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Montagu MFA (1949) Paget's disease (osteitis deformans) and hereditary. Am J Hum Genet 1: 94–95

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Hocking L et al. (2000) Familial Paget's disease of bone: patterns of inheritance and frequency of linkage to chromosome 18q. Bone 26: 577–580

    Article  CAS  PubMed  Google Scholar 

  15. Morales-Piga AA et al. (1995) Frequency and characteristics of familial aggregation of Paget's disease of bone. J Bone Miner Res 10: 663–670

    Article  CAS  PubMed  Google Scholar 

  16. Siris ES et al. (1991) Familial aggregation of Paget's disease of bone. J Bone Miner Res 6:495–500

    Article  CAS  PubMed  Google Scholar 

  17. Sofaer JA et al. (1983) A family study of Paget's disease of bone. J Epidemiol Community Health 37: 226–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Eekhoff EW et al. (2004) Familial Paget's disease in The Netherlands: occurrence, identification of new mutations in the sequestosome 1 gene, and their clinical associations. Arthritis Rheum 50: 1650–1654

    Article  CAS  PubMed  Google Scholar 

  19. Hocking L et al. (2002). Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease. Hum Mol Genet 11: 2735–2739

    Article  CAS  PubMed  Google Scholar 

  20. Barker DJ (1984) The epidemiology of Paget's disease of bone. Br Med Bull 40: 396–400

    Article  CAS  PubMed  Google Scholar 

  21. Osterberg PH et al. (1988) Familial expansile osteolysis. A new dysplasia. J Bone Joint Surg Br 70: 255–260

    Article  CAS  PubMed  Google Scholar 

  22. Nakatsuka K (2003) Phenotypic characterization of early onset Paget's disease of bone caused by a 27-bp duplication in the TNFRSF11A gene. J Bone Miner Res 18: 1381–1385

    Article  CAS  PubMed  Google Scholar 

  23. Whyte MP and Hughes AE (2002) Expansile skeletal hyperphosphatasia is caused by a 15-base pair tandem duplication in TNFRSF11A encoding RANK and is allelic to familial expansile osteolysis. J Bone Miner Res 17: 26–29

    Article  CAS  PubMed  Google Scholar 

  24. Whyte MP et al. (2002) Osteoprotegerin deficiency and juvenile Paget's disease. N Engl J Med 347: 175–184

    Article  CAS  PubMed  Google Scholar 

  25. Kovach MJ et al. (2001) Clinical delineation and localization to chromosome 9p13.3-p12 of a unique dominant disorder in four families: hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia. Mol Genet Metab 74: 458–475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tilyard MW et al. (1982) A probable linkage between familial Paget's disease and the HLA loci. Aust NZ J Med 12: 498–500

    Article  CAS  Google Scholar 

  27. Hughes AE et al. (1994) Genetic linkage of familial expansile osteolysis to chromosome 18q. Hum Mol Genet 3: 359–361

    Article  CAS  PubMed  Google Scholar 

  28. Laurin N et al. (2001) Paget disease of bone: mapping of two loci at 5q35-qter and 5q31. Am J Hum Genet 69: 528–543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hocking LJ et al. (2001) Genomewide search in familial Paget disease of bone shows evidence of genetic heterogeneity with candidate loci on chromosomes 2q36, 10p13, and 5q35. Am J Hum Genet 69: 1055–1061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Good DA et al. (2001) Linkage of Paget disease of bone to a novel region on human chromosome 18q23. Am J Hum Genet 70: 517–525

    Article  PubMed  PubMed Central  Google Scholar 

  31. Cundy T et al. (2002) A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype. Hum Mol Genet 11: 2119–2127

    Article  CAS  PubMed  Google Scholar 

  32. Teitelbaum SL (2000) Bone resorption by osteoclasts. Science 289: 1504–1508

    Article  CAS  PubMed  Google Scholar 

  33. Hughes AE et al. (2000) Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet 24: 45–48

    Article  CAS  PubMed  Google Scholar 

  34. Palenzuela L et al. (2002) Familial expansile osteolysis in a large Spanish kindred resulting from an insertion mutation in the TNFRSF11A gene. J Med Genet 39: E67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Johnson-Pais TL et al. (2003) Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis. J Bone Miner Res 18: 376–380

    Article  CAS  PubMed  Google Scholar 

  36. Sparks AB et al. (2001) Mutation screening of the TNFRSF11A gene encoding receptor activator of NF kappa B (RANK) in familial and sporadic Paget's disease of bone and osteosarcoma. Calcif Tissue Int 68: 151–155

    Article  CAS  PubMed  Google Scholar 

  37. Wuyts W et al. (2001) Evaluation of the role of RANK and OPG genes in Paget's disease of bone. Bone 28: 104–107

    Article  CAS  PubMed  Google Scholar 

  38. Nellissery MJ et al. (1998) Evidence for a novel osteosarcoma tumor-suppressor gene in the chromosome 18 region genetically linked with Paget disease of bone. Am J Hum Genet 63: 817–824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. B Chong (2003) Idiopathic hyperphosphatasia and TNFRSF11B mutations: relationships between phenotype and genotype. J Bone Miner Res 18: 2095–2104

    Article  CAS  PubMed  Google Scholar 

  40. Hocking LJ et al. (2004) Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: genotype phenotype correlation, functional analysis and structural consequences. J Bone Miner Res 19: 1122–1127

    Article  CAS  PubMed  Google Scholar 

  41. Good DA et al. (2004) Identification of SQSTM1 mutations in familial Paget's disease in Australian pedigrees. Bone 35: 277–282

    Article  CAS  PubMed  Google Scholar 

  42. Johnson-Pais TL et al. (2003) Three novel mutations in SQSTM1 identified in familial Paget's disease of bone. J Bone Miner Res 18: 1748–1753

    Article  CAS  PubMed  Google Scholar 

  43. Beyens G et al. (2004) Evaluation of the role of the SQSTM1 gene in sporadic Belgian patients with Paget's disease. Calcif Tissue Int 75: 144–152

    Article  CAS  PubMed  Google Scholar 

  44. Ciani B et al. (2003) Structure of the UBA domain of p62 (SQSTM1) and implications for mutations which cause Paget's disease of bone. J Biol Chem 278: 37409–37412

    Article  CAS  PubMed  Google Scholar 

  45. Cavey JR et al. (2005) Loss of ubiquitin-binding associated with Paget's disease of bone p62 (SQSTM1) mutations. J Bone Miner Res 20: 619–624

    Article  CAS  PubMed  Google Scholar 

  46. Layfield R and Hocking LJ (2004) SQSTM1 and Paget's disease of bone. Calcif Tissue Int 75: 347–357

    Article  CAS  PubMed  Google Scholar 

  47. Chen ZJ (2005) Ubiquitin signalling in the NFkB pathway. Nat Cell Biol 7: 758–766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Laurin N et al. (2002) Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet 70: 1582–1588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lucas GJ et al. (2005) Ubiquitin-associated domain mutations of SQSTM1 in Paget's disease of bone: evidence for a founder effect in patients of British descent. J. Bone Miner Res 20: 227–231

    Article  CAS  PubMed  Google Scholar 

  50. Duran A et al. (2004) The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis. Dev Cell 6: 303–309

    Article  CAS  PubMed  Google Scholar 

  51. Daroszewska A et al. (2004) Susceptibility to Paget's disease of bone is influenced by a common polymorphic variant of osteoprotegerin. J Bone Miner Res 19: 1506–1511

    Article  CAS  PubMed  Google Scholar 

  52. Wang Q et al. (2004) Molecular perspectives on p97-VCP: progress in understanding its structure and diverse biological functions. J Struct Biol 146: 44–57

    Article  CAS  PubMed  Google Scholar 

  53. Watts GD et al. (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36: 377–381

    Article  CAS  PubMed  Google Scholar 

  54. Dai RM et al. (1998) Involvement of valosin-containing protein, an ATPase co-purified with IκBα and 26S proteasome, in ubiquitin-proteasome-mediated degradation of IκBα. J Biol Chem 273: 3562–3573

    Article  CAS  PubMed  Google Scholar 

  55. Lucas GJA et al. (2006) Evaluation of the role of valosin-containing protein in the pathogenesis of familial and sporadic Paget's disease of bone. Bone 38: 280–285

    Article  CAS  PubMed  Google Scholar 

  56. Langston AL and Ralston SH (2004) Management of Paget's disease of bone. Rheumatology (Oxford) 43: 955–959

    Article  CAS  Google Scholar 

  57. Pei Y (2001) A 'two-hit' model of cystogenesis in autosomal dominant polycystic kidney disease? Trends Mol Med 7: 151–156

    Article  CAS  PubMed  Google Scholar 

  58. Guise TA and Mundy GR (1998) Cancer and bone. Endocr Rev 19: 18–54

    CAS  PubMed  Google Scholar 

  59. Cody JD et al. (1997) Genetic linkage of Paget disease of the bone to chromosome 18q. Am J Hum Genet 61: 1117–1122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Good DA et al. (2004) Identification of SQSTM1 mutations in familial Paget's disease in Australian pedigrees. Bone 35: 277–282

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by a program grant to SH Ralston from the Arthritis Research Campaign, UK and by a Medical Research Council clinical training fellowship to A Daroszewska.

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Authors and Affiliations

  1. Lecturer in Rheumatology at the University of Edinburgh, UK

    Anna Daroszewska

  2. Professor of Rheumatology at the University of Edinburgh, UK

    Stuart H Ralston

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Correspondence to Stuart H Ralston.

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Daroszewska, A., Ralston, S. Mechanisms of Disease: genetics of Paget's disease of bone and related disorders. Nat Rev Rheumatol 2, 270–277 (2006). https://doi.org/10.1038/ncprheum0172

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