Hostname: page-component-78c5997874-t5tsf Total loading time: 0 Render date: 2024-11-09T06:53:20.839Z Has data issue: false hasContentIssue false
  • English
  • Français

The molecular pathogenesis of Paget disease of bone

Published online by Cambridge University Press:  01 October 2007

Robert Layfield
Robert Layfield
Affiliation:
School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK. Tel: +44 (0)115 8230107; Fax: +44 (0)115 9709969; E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Paget disease of bone (PDB) is a condition characterised by increased bone remodelling at discrete lesions throughout the skeleton. The primary cellular abnormality in PDB involves a net increase in the activity of bone-resorbing osteoclasts, with a secondary increase in bone-forming osteoblast activity. Genetic factors are known to play an important role, with mutations affecting different components of the RANK–NF-κB signalling pathway having been identified in patients with PDB and related disorders. Whilst the disease mechanism in these cases is likely to involve aberrant RANK-mediated osteoclast NF-κB signalling, the precise relationship between other potential contributors, such as viruses and environmental factors, and the molecular pathogenesis of PDB is less clear. This review considers the roles of these different factors in PDB, and concludes that a fuller understanding of their contributions to disease aetiology is likely to be central to future advances in the clinical management of this debilitating skeletal disorder.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 9 , Issue 27 , September 2007 , pp. 1 - 13
Copyright
Copyright © Cambridge University Press 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Roberts, S. (1989) Sir James Paget – the Rise of Clinical Surgery, Royal Society of Medicine Services Ltd, LondonGoogle Scholar
2Rogers, J., Jeffrey, D.R. and Watt, I. (2002) Paget's disease in an archeological population. J Bone Miner Res 17, 1127-1134CrossRefGoogle Scholar
3Cooper, C. et al. (1999) The epidemiology of Paget's disease in Britain: is the prevalence decreasing? J Bone Miner Res 14, 192-197CrossRefGoogle ScholarPubMed
4Daroszewska, A. and Ralston, S.H. (2005) Genetics of Paget's disease of bone. Clin Sci (Lond) 109, 257-263CrossRefGoogle ScholarPubMed
5Kanis, J.A. (1992) Pathophysiology and Treatment of Paget's Disease of Bone, Martin Dunitz, LondonGoogle Scholar
6van Staa, T.P. et al. (2002) Incidence and natural history of Paget's disease of bone in England and Wales. J Bone Miner Res 17, 465-471CrossRefGoogle ScholarPubMed
7Huvos, A.G. (1986) Osteogenic sarcoma of bones and soft tissues in older persons. A clinicopathologic analysis of 117 patients older than 60 years. Cancer 57, 1442-14493.0.CO;2-3>CrossRefGoogle Scholar
8Reddy, S.V. et al. (1999) Cell biology of Paget's disease. J Bone Miner Res 14, Suppl 2, 3-8CrossRefGoogle ScholarPubMed
9Gardner, M.J., Guyer, P.B. and Barker, D.J. (1978) Radiological prevalence of Paget's disease of bone in British migrants to Australia. Br Med J 1, 1655-1657CrossRefGoogle ScholarPubMed
10Siris, E.S. (1994) Epidemiological aspects of Paget's disease: family history and relationship to other medical conditions. Semin Arthritis Rheum 23, 222-225CrossRefGoogle ScholarPubMed
11Sofaer, J.A., Holloway, S.M. and Emery, A.E. (1983) A family study of Paget's disease of bone. J Epidemiol Community Health 37, 226-231CrossRefGoogle ScholarPubMed
12Morales-Piga, A.A. et al. (1995) Frequency and characteristics of familial aggregation of Paget's disease of bone. J Bone Miner Res 10, 663-670CrossRefGoogle ScholarPubMed
13Hocking, L. et al. (2000) Familial Paget's disease of bone: patterns of inheritance and frequency of linkage to chromosome 18q. Bone 26, 577-580CrossRefGoogle ScholarPubMed
14Haslam, S.I. et al. (1998) Paget's disease of bone: evidence for a susceptibility locus on chromosome 18q and for genetic heterogeneity. J Bone Miner Res 13, 911-917CrossRefGoogle ScholarPubMed
15Layfield, R. and Hocking, L.J. (2004) SQSTM1 and Paget's disease of bone. Calcif Tissue Int 75, 347-357CrossRefGoogle ScholarPubMed
16Watts, G.D. 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, 377-381CrossRefGoogle ScholarPubMed
17Duran, A. et al. (2004) The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis. Dev Cell 6, 303-309CrossRefGoogle ScholarPubMed
18Teitelbaum, S.L. and Ross, F.P. (2003) Genetic regulation of osteoclast development and function. Nat Rev Genet 4, 638-649CrossRefGoogle Scholar
19Laurin, N. et al. (2002) Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet 70, 1582-1588CrossRefGoogle ScholarPubMed
20Hocking, L.J. et al. (2002) Domain specific mutations in Sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease. Hum Mol Genet 11, 2735-2739CrossRefGoogle ScholarPubMed
21Johnson-Pais, T.L. et al. (2003) Three novel mutations in SQSTM1 identified in familial Paget's disease of bone. J Bone Miner Res 18, 1748-1753CrossRefGoogle ScholarPubMed
22Good, D.A. et al. (2004) Identification of SQSTM1 mutations in familial Paget's disease in Australian pedigrees. Bone 35, 277-282CrossRefGoogle ScholarPubMed
23Beyens, G. et al. (2004) Evaluation of the role of the SQSTM1 gene in sporadic Belgian patients with Paget's disease. Calcif Tissue Int 75, 144-152CrossRefGoogle ScholarPubMed
24Eekhoff, E.W. 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, 1650-1654CrossRefGoogle ScholarPubMed
25Falchetti, A. et al. (2004) Two novel mutations at exon 8 of Sequestosome 1 gene (SQSTM1) in an Italian serie of patients affected by Paget's disease of bone (PDB). J Bone Miner Res 19, 1013-1017CrossRefGoogle Scholar
26Hocking, L.J. 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, 1122-1127CrossRefGoogle ScholarPubMed
27Beyens, G. et al. (2006) Identification and molecular characterization of a novel splice-site mutation (G1205C) in the SQSTM1 gene causing Paget's disease of bone in an extended American family. Calcif Tissue Int 79, 281-288CrossRefGoogle Scholar
28Rea, S.L. et al. (2006) A novel mutation (K378X) in the sequestosome 1 gene associated with increased NF-kappaB signalling and Paget's disease of bone with a severe phenotype. J Bone Miner Res 21, 1136-1145CrossRefGoogle ScholarPubMed
29Collet, C. et al. (2007) Paget's disease of bone in the French population: novel SQSTM1 mutations, functional analysis, and genotype-phenotype correlations. J Bone Miner Res 22, 310-317CrossRefGoogle ScholarPubMed
30Hughes, A.E. et al. (2000) Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet 24, 45-48CrossRefGoogle ScholarPubMed
31Whyte, M.P. and Hughes, A.E. (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, 26-29CrossRefGoogle ScholarPubMed
32Nakatsuka, K., Nishizawa, K. and Ralston, S.H. (2003) Phenotypic characterisation of early onset Paget's disease of bone caused by a 27 bp duplication in the TNFRSF11A gene. J Bone Miner Res 18, 1381-1385CrossRefGoogle ScholarPubMed
33Whyte, M.P. et al. (2002) Osteoprotegerin deficiency and juvenile Paget's disease. N Engl J Med 347, 175-184CrossRefGoogle ScholarPubMed
34Cundy, T. et al. (2002) A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype. Hum Mol Genet 11, 2119-2127CrossRefGoogle ScholarPubMed
35Asai, T. et al. (2002) VCP (p97) regulates NFkappaB signaling pathway, which is important for metastasis of osteosarcoma cell line. Jpn J Cancer Res 93, 296-304CrossRefGoogle ScholarPubMed
36Hsu, H. et al. (1999) Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci U S A 96, 3540-3545CrossRefGoogle ScholarPubMed
37Galibert, L. et al. (1998) The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-kappaB, a member of the TNFR superfamily. J Biol Chem 273, 34120-341277CrossRefGoogle ScholarPubMed
38Ye, H. et al. (2002) Distinct molecular mechanism for initiating TRAF6 signalling. Nature 418, 443-447CrossRefGoogle ScholarPubMed
39Deng, L. et al. (2000) Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103, 351-361CrossRefGoogle Scholar
40Chen, Z.J. (2005) Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol 7, 758-765CrossRefGoogle ScholarPubMed
41Andersen, K.M., Hofmann, K. and Hartmann-Petersen, R. (2005) Ubiquitin-binding proteins: similar, but different. Essays Biochem 41, 49-67CrossRefGoogle Scholar
42Kanayama, A. et al. (2004) TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains. Mol Cell 15, 535-548CrossRefGoogle ScholarPubMed
43Jimi, E. et al. (2004) Selective inhibition of NF-kappa B blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo. Nat Med 10, 617-624CrossRefGoogle ScholarPubMed
44Yip, K.H. et al. (2006) p62 ubiquitin binding-associated domain mediated the receptor activator of nuclear factor-kappaB ligand-induced osteoclast formation: a new insight into the pathogenesis of Paget's disease of bone. Am J Pathol 169, 503-514CrossRefGoogle ScholarPubMed
45Raasi, S. et al. (2005) Diverse polyubiquitin interaction properties of ubiquitin-associated domains. Nat Struct Mol Biol 12, 708-714CrossRefGoogle ScholarPubMed
46Vadlamudi, R.K. et al. (1996) p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck, belongs to a new class of ubiquitin-binding proteins. J Biol Chem 271, 20235-20237CrossRefGoogle ScholarPubMed
47Layfield, R. et al. (2006) p62 mutations, ubiquitin recognition and Paget's disease of bone. Biochem Soc Trans 34, 735-737CrossRefGoogle ScholarPubMed
48Cavey, J.R. et al. (2005) Loss of ubiquitin-binding associated with Paget's disease of bone p62 (SQSTM1) mutations. J Bone Miner Res 20, 619-624CrossRefGoogle ScholarPubMed
49Cavey, J.R. et al. (2006) Loss of ubiquitin binding is a unifying mechanism by which mutations of SQSTM1 cause Paget's disease of bone. Calcif Tissue Int 78, 271-277CrossRefGoogle ScholarPubMed
50Wooten, M.W. et al. (2005) The p62 scaffold regulates nerve growth factor-induced NF-kappaB activation by influencing TRAF6 polyubiquitination. J Biol Chem 280, 35625-35629CrossRefGoogle ScholarPubMed
51Takayanagi, H. et al. (2000) T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature 408, 600-605CrossRefGoogle ScholarPubMed
52Menaa, C. et al. (2000) Enhanced RANK ligand expression and responsivity of bone marrow cells in Paget's disease of bone. J Clin Invest 105, 1833-1938CrossRefGoogle ScholarPubMed
53Hofbauer, L.C. and Heufelder, A.E. (2001) Role of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in bone cell biology. J Mol Med 79, 243-253CrossRefGoogle ScholarPubMed
54Martini, G. et al. (2007) Serum OPG and RANKL levels before and after intravenous bisphosphonate treatment in Paget's disease of bone. Bone 40, 457-463CrossRefGoogle ScholarPubMed
55Halawani, D. and Latterich, M. (2006) p97: The cell's molecular purgatory? Mol Cell 22, 713-717CrossRefGoogle ScholarPubMed
56Weihl, C.C. et al. (2006) Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation. Hum Mol Genet 15, 189-199CrossRefGoogle ScholarPubMed
57Dai, R.M. et al. (1998) Involvement of valosin-containing protein, an ATPase Co-purified with IkappaBalpha and 26S proteasome, in ubiquitin-proteasome-mediated degradation of IkappaBalpha. J Biol Chem 273, 3562-3573CrossRefGoogle Scholar
58Layfield, R. et al. (2001) The ubiquitin protein catabolic disorders. Neuropathol Appl Neurobiol 27, 171-179CrossRefGoogle ScholarPubMed
59Reddy, S.V. (2006) Etiologic factors in Paget's disease of bone. Cell Mol Life Sci 63, 391-398CrossRefGoogle ScholarPubMed
60Harvey, L. et al. (1982) Ultrastructural features of the osteoclasts from Paget's disease of bone in relation to a viral etiology. J Clin Pathol 35, 771-779CrossRefGoogle Scholar
61Mills, B.G. and Singer, F.R. (1976) Nuclear inclusions in Paget's disease of bone. Science 194, 201-202CrossRefGoogle ScholarPubMed
62Mills, B.G. et al. (1984) Evidence for both respiratory synctial virus and measles virus antigens in the osteoclasts of patients with Paget's disease of bone. Clin Orthop Relat Res 183, 303-311CrossRefGoogle Scholar
63Rebel, A. et al. (1980) Bone tissue in Paget's disease of bone. Ultrastructure and immunocytology. Arthritis Rheum 23, 1104-1144CrossRefGoogle ScholarPubMed
64Reddy, S.V. et al. (1999) Measles virus nucleocapsid transcript expression is not restricted to the osteoclast lineage in patients with Paget's disease of bone. Exp Hematol 27, 1528-1532CrossRefGoogle ScholarPubMed
65Friedrichs, W.E. et al. (2002) Sequence analysis of measles virus nucleocapsid transcripts in patients with Paget's disease. J Bone Miner Res 17, 145-151CrossRefGoogle ScholarPubMed
66Helfrich, M.H. et al. (2000) A negative search for a paramyxoviral etiology of Paget's disease of bone: molecular, immunological, and ultrastructural studies in UK patients. J Bone Miner Res 15, 2315-2329CrossRefGoogle ScholarPubMed
67Ralston, S.H. et al. (2007) Multicenter blinded analysis of RT-PCR detection methods for paramyoviruses in relation to Paget's disease of bone. J Bone Miner Res 22, 569-577CrossRefGoogle Scholar
68Kurihara, N. et al. (2000) Osteoclasts expressing the measles virus nucleocapsid gene display a pagetic phenotype. J Clin Invest 105, 607-614CrossRefGoogle ScholarPubMed
69Menaa, C. et al. (2000) 1,25-Dihydroxyvitamin D3 hypersensitivity of osteoclast precursors from patients with Paget's disease. J Bone Miner Res 15, 228-236CrossRefGoogle ScholarPubMed
70Kurihara, N. et al. (2004) Role of TAFII-17, a VDR binding protein, in the increased osteoclast formation in Paget's disease. J. Bone Miner Res 19, 1154-1164CrossRefGoogle ScholarPubMed
71Kurihara, N. et al. (2006) Experimental models of Paget's disease. J Bone Miner Res 21, Suppl 2, 55-57CrossRefGoogle ScholarPubMed
72Kurihara, N. et al. (2006) Expression of the measles virus nucleocapsid protein in osteoclasts in vivo induces Paget's disease like bone lesions in mice. J Bone Miner Res 21, 446-455CrossRefGoogle ScholarPubMed
73Mee, A.P. et al. (1998) Detection of canine distemper virus in 100% of Paget's disease samples by in situ reverse transcriptase polymerase chain reaction. Bone 23, 171-175CrossRefGoogle ScholarPubMed
74Selby, P.L., Davies, M. and Mee, A.P. (2006) Canine distemper virus induces human osteoclastogenesis through NF-kappB and sequestosome1/p62 activation. J Bone Miner Res 21, 1750-1756CrossRefGoogle Scholar
75Cundy, T. (2006) Is the prevalence of Paget's disease of bone decreasing? J Bone Miner Res 21, Suppl 2, 9-13CrossRefGoogle ScholarPubMed
76Bolland, M.J. et al. (2007) Delayed development of Paget's disease in offspring inheriting SQSTM1 mutations. J Bone Miner Res 22, 411-415CrossRefGoogle ScholarPubMed
77Siris, E.S. (1994) Epidemiological aspects of Paget's disease: family history and relationship to other medical conditions. Semin Arthritis Rheum 23, 222-225CrossRefGoogle ScholarPubMed
78Lever, J.H. (2002) Paget's disease of bone in Lancashire and arsenic pesticide in cotton mill wastewater: a speculative hypothesis. Bone 31, 434-436CrossRefGoogle ScholarPubMed
79Aono, J. et al. (2003) Activation of Nrf2 and accumulation of ubiquitinated A170 by arsenic in osteoblasts. Biochem Biophys Res Commun 305, 271-277CrossRefGoogle ScholarPubMed
80Coxon, F.P., Thompson, K. and Rogers, M.J. (2006) Recent advances in understanding the mechanism of action of bisphosphonates. Curr Opin Pharmacol 6, 307-312CrossRefGoogle ScholarPubMed
81Corrado, A., Santoro, N. and Cantatore, F.P. (2007) Extra-skeletal effects of bisphosponates. Joint Bone Spine 74, 32-38CrossRefGoogle Scholar
82Hoskins, D. (2006) Pharmacological therapy of Paget's and other metabolic bone diseases. Bone 38, Suppl 2, 3-7CrossRefGoogle Scholar
83Langston, A.L. et al. (2007) Clinical determinants of quality of life in Paget's disease of bone. Calcif Tissue Int 80, 1-9CrossRefGoogle ScholarPubMed
84Vaananen, K. (2005) Mechanism of osteoclast mediated bone resorption- rationale for the design of new therapeutics. Adv Drug Deliv Rev 57, 959-971CrossRefGoogle ScholarPubMed
85Tat, S.K. et al. (2006) OPG/membranous-RANKL complex is internalized via the clathrin pathway before a lysosomal and a proteasomal degradation. Bone 39, 706-715CrossRefGoogle Scholar
86McClung, M.R. et al. (2006) Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 354, 821-831CrossRefGoogle ScholarPubMed
87Cundy, T. et al. (2005) Recombinant osteoprotegerin for juvenile Paget's disease. N Engl J Med 353, 918-923CrossRefGoogle ScholarPubMed
88Leach, R.J. et al. (2006) Clinical and cellular phenotypes associated with Sequestosome 1 (SQSTM1) mutations. J Bone Miner Res 21, Suppl 2, 45-50CrossRefGoogle ScholarPubMed
89Morisette, J., Laurin, N. and Brown, J.P. (2006) Sequestosome 1: mutation frequencies, haplotypes and phenotypes in familial Paget's disease of bone. J Bone Miner Res 21, Suppl 2, 38-44CrossRefGoogle Scholar
90Kurihara, N. et al. (2007) Mutation of the sequestosome 1 (p62) gene increases osteoclastogenesis but does not induce Paget disease. J Clin Invest 117, 133-142CrossRefGoogle Scholar

Further reading, resources and contacts

The UK National Association for the Relief of Paget's Disease (NARPD) website contains useful information for patients, researchers and clinicians:

The Online Mendelian Inheritance in Man (OMIM) database contains further information related to genetic mutations in PDB and PDB-like syndromes:

http://www.paget.org.uk/Google Scholar
http://www.paget.org/Google Scholar
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602080Google Scholar
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601530Google Scholar
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=174810Google Scholar
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603499Google Scholar
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=239000Google Scholar
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602643Google Scholar
Evans, P.C. (2005) Regulation of pro-inflammatory signalling networks by ubiquitin: identification of novel targets for anti-inflammatory drugs. Expert Rev Mol Med 7, 1-19CrossRefGoogle ScholarPubMed
http://www.paget.org.uk/Google Scholar
http://www.paget.org/Google Scholar
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602080Google Scholar
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601530Google Scholar
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=174810Google Scholar
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603499Google Scholar
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=239000Google Scholar
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602643Google Scholar
Evans, P.C. (2005) Regulation of pro-inflammatory signalling networks by ubiquitin: identification of novel targets for anti-inflammatory drugs. Expert Rev Mol Med 7, 1-19CrossRefGoogle ScholarPubMed