New insights into the role of sequestosome 1/p62 mutant proteins in the pathogenesis of paget's disease of bone

Endocrine Reviews

Volumn 34, Issue 4, 2013, Pages 501-524

  Rea, Sarah L ^a,b   Walsh, John P ^b,c   Layfield, Robert ^d   Ratajczak, Thomas ^a,b   Xu Jiake, J ^e  

^a UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

^b SIR CHARLES GAIRDNER HOSPITAL   (Australia)

^c UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

^d UNIVERSITY OF NOTTINGHAM   (United Kingdom)

^e UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

Author keywords

Apoptosis; Autophagy; NF B; p62; Paget's disease of bone; RANK RANKL; Sequestosome; Ubiquitin

Indexed keywords

CASPASE; CELL PROTEIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; KELCH LIKE ECH ASSOCIATED PROTEIN 1; MUTANT PROTEIN; PROTEIN P62; SEQUESTOSOME 1; TRANSCRIPTION FACTOR NRF2; UNCLASSIFIED DRUG; ZOLEDRONIC ACID;

APOPTOSIS; AUTOPHAGY; CELL DIFFERENTIATION; CELL SURVIVAL; GENE MUTATION; GENETIC PREDISPOSITION; GENETIC SCREENING; HUMAN; MOLECULAR INTERACTION; NONHUMAN; OSTEOCLAST; OSTEOLYSIS; OXIDATIVE STRESS; PAGET BONE DISEASE; PATHOGENESIS; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN INDUCTION; REVIEW; SIGNAL TRANSDUCTION;

EID: 84884271969     PISSN: 0163769X     EISSN: None     Source Type: Journal    
DOI: 10.1210/er.2012-1034     Document Type: Review

References (262)

1. Paget J. On a form of chronic inflammation of bones (osteitis deformans). Med Chir Trans. 1877;60:37-64.
2. Cooper C, Dennison E, Schafheutle K, Kellingray S, Guyer P, Barker D. Epidemiology of Paget's disease of bone. Bone. 1999;24:3S-5S.
3. van Staa TP, Selby P, Leufkens HG, Lyles K, Sprafka JM, Cooper C. Incidence and natural history of Paget's disease of bone in England and Wales. J Bone Miner Res. 2002; 17:465-471.
4. Hamdy R. Paget's disease of bone: assessment and management. London, UK: Praegar Publishers; 1981:203.
5. Cooper C, Harvey NC, DennisonEM,van Staa TP. Update on the epidemiology of Paget's disease of bone. J Bone Miner Res. 2006;21(suppl 2):P3-P8.
6. Eekhoff ME, van der Klift M, Kroon HM, et al. Paget's disease of bone in The Netherlands: a population-based radiological and biochemical survey-the Rotterdam Study. J Bone Miner Res. 2004;19:566-570.
7. Gennari L, Di Stefano M, Merlotti D, et al. Prevalence of Paget's disease of bone in Italy. J Bone Miner Res. 2005; 20:1845-1850.
8. Mays S. Archaeological skeletons support a northwest European origin for Paget's disease of bone. J Bone Miner Res. 2010;25:1839-1841.
9. Cooper C, Schafheutle K, Dennison E, Kellingray S, Guyer P, Barker D. The epidemiology of Paget's disease in Britain: is the prevalence decreasing? J Bone Miner Res. 1999;14: 192-197.
10. Cundy T, Wattie D, Busch S, Rutland M, Ibbertson HK. Paget's disease inNewZealand: is it changing? Bone. 1999; 24:7S-9S.
11. Doyle T, Gunn J, Anderson G, Gill M, Cundy T. Paget's disease in New Zealand: evidence for declining prevalence. Bone. 2002;31:616-619.
12. Poor G, Donath J, Fornet B, Cooper C. Epidemiology of Paget's disease in Europe: the prevalence is decreasing. J Bone Miner Res. 2006;21:1545-1549.
13. Tiegs RD, Lohse CM, Wollan PC, Melton LJ. Long-term trends in the incidence of Paget's disease of bone. Bone. 2000;27:423-427.
14. Seitz S, Priemel M, Zustin J, et al. Paget's disease of bone: histologic analysis of 754 patients. J Bone Miner Res. 2009; 24:62-69.
15. Whyte MP. Paget's disease of bone and genetic disorders of RANKL/OPG/RANK/NF-κB signaling. Ann NY Acad Sci. 2006;1068:143-164.
16. Ralston SH, Langston AL, Reid IR. Pathogenesis and management of Paget's disease of bone. Lancet. 2008;372:155-163.
17. Menaa C, Reddy SV, Kurihara N, et al. Enhanced RANK ligand expression and responsivity of bone marrow cells in Paget's disease of bone. J Clin Invest. 2000;105:1833-1838.
18. Naot D, Bava U, Matthews B, et al. Differential gene expression in cultured osteoblasts and bone marrow stromal cells from patients with Paget's disease of bone. J Bone Miner Res. 2007;22:298-309.
19. Hiruma Y, Kurihara N, Subler MA, et al. A SQSTM1/p62 mutation linked to Paget's disease increases the osteoclastogenic potential of the bone microenvironment.HumMol Genet. 2008;17:3708-3719.
20. Meunier PJ, Salson C, Mathieu L, et al. Skeletal distribution and biochemical parameters of Paget's disease. Clin Orthop Relat Res. 1987;217:37-44.
21. Walsh JP, Attewell R, Stuckey BG, et al. Treatment of Paget's disease of bone: a survey of clinical practice in Australia. Bone. 2008;42:1219-1225.
22. Melton LJ III, Tiegs RD, Atkinson EJ, O'FallonWM.Fracture riskamongpatients with Paget's disease: a populationbased cohort study. J Bone Miner Res. 2000;15:2123-2128.
23. Rendina D, Gennari L, De Filippo G, et al. Evidence for increased clinical severity of familial and sporadic Paget's disease of bone in Campania, southern Italy. J Bone Miner Res. 2006;21:1828-1835.
24. Singer FR, Mills BG. Giant cell tumor arising in Paget's disease of bone. Recurrences after 36 years. Clin Orthop Relat Res. 1993;293:293-301.
25. Hansen MF, Seton M, Merchant A. Osteosarcoma in Paget's disease of bone. J Bone Miner Res. 2006;21(suppl 2): P58-P63.
26. Gold DT, Boisture J, Shipp KM, Pieper CF, Lyles KW. Paget's disease of bone and quality of life. J Bone Miner Res. 1996;11:1897-1904.
27. Langston AL, Campbell MK, Fraser WD, Maclennan G, Selby P, Ralston SH. Clinical determinants of quality of life in Paget's disease of bone. Calcif Tissue Int. 2007;80:1-9.
28. SetonM,MosesAM,BodeRK,Schwartz C. Paget's disease of bone: the skeletal distribution, complications and quality of life as perceived by patients.Bone. 2011;48:281-285.
29. Wermers RA, Tiegs RD, Atkinson EJ, Achenbach SJ, Melton LJ III. Morbidity and mortality associated with Paget's disease of bone: a population-based study. J Bone Miner Res. 2008;23:819-825.
30. Helfrich MH, Hobson RP, Grabowski PS, et al. A negative search for a paramyxoviral etiology of Paget's disease of bone: molecular, immunological, and ultrastructural studies inUKpatients. J Bone Miner Res. 2000;15:2315-2329.
31. Mills BG, Singer FR. Nuclear inclusions in Paget's disease of bone. Science. 1976;194:201-202.
32. Reddy SV, Menaa C, Singer FR, et al. Measles virus nucleocapsid transcript expression is not restricted to the osteoclast lineage in patients with Paget's disease of bone. Exp Hematol. 1999;27:1528-1532.
33. Roodman GD. Mechanisms of abnormal bone turnover in Paget's disease. Bone. 1999;24:39S-40S.
34. Gennari L, Gianfrancesco F, Di Stefano M, et al. SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone. J Bone Miner Res. 2010;25:1375-1384.
35. Lopez-Abente G, Morales-Piga A, Elena-Ibanez A, Rey-Rey JS, Corres-Gonzalez J. Cattle, pets, and Paget's disease of bone. Epidemiology. 1997;8:247-251.
36. Rendina D, Gianfrancesco F, De Filippo G, et al. Epidemiological, clinical, and genetic characteristics of Paget's disease of bone in a rural area of Calabria, Southern Italy. J Endocrinol Invest. 2010;33:519-525.
37. Gordon MT, Anderson DC, Sharpe PT. Canine distemper virus localised in bone cells of patients with Paget's disease. Bone. 1991;12:195-201.
38. Gordon MT, Mee AP, Anderson DC, Sharpe PT. Canine distemper virus transcripts sequenced from pagetic bone. Bone Miner. 1992;19:159-174.
39. Hoyland JA, Dixon JA, Berry JL, Davies M, Selby PL, Mee AP. A comparison of in situ hybridisation, reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ-RT-PCR for the detection of canine distemper virus RNA in Paget's disease. J Virol Methods. 2003;109:253-259.
40. Mee AP, Dixon JA, Hoyland JA, Davies M, Selby PL, MawerEB. Detection of canine distemper virus in100%of Paget's disease samples by in situ-reverse transcriptasepolymerase chain reaction. Bone. 1998;23:171-175.
41. Selby PL, Davies M, Mee AP. Canine distemper virus induces human osteoclastogenesis through NF-κB and sequestosome 1/P62 activation. J Bone Miner Res. 2006;21: 1750-1756.
42. Friedrichs WE, Reddy SV, Bruder JM, et al. Sequence analysis of measles virus nucleocapsid transcripts in patients with Paget's disease. J Bone Miner Res. 2002;17:145-151.
43. Merchant A, Smielewska M, Patel N, et al. Somatic mutations in SQSTM1 detected in affected tissues from patients with sporadic Paget's disease of bone. J Bone Miner Res. 2009;24:484-494.
44. Kurihara N, Zhou H, Reddy SV, et al. Expression of measles virus nucleocapsid protein in osteoclasts induces Paget's disease-like bone lesions in mice. J Bone Miner Res. 2006;21:446-455.
45. Matthews BG, AfzalMA,Minor PD, et al. Failure to detect measles virus ribonucleic acid in bone cells from patients with Paget's disease. J Clin Endocrinol Metab. 2008;93: 1398-1401.
46. Ooi CG, Walsh CA, Gallagher JA, Fraser WD. Absence of measles virus and canine distemper virus transcripts in long-term bone marrow cultures from patients with Paget's disease of bone. Bone. 2000;27:417-421.
47. Ralston SH, Afzal MA, Helfrich MH, et al. Multicenter blinded analysis of RT-PCR detection methods for paramyxoviruses in relation to Paget's disease of bone. J Bone Miner Res. 2007;22:569-577.
48. Ralston SH, Digiovine FS, Gallacher SJ, Boyle IT, Duff GW. Failure to detect paramyxovirus sequences in Paget's disease of bone using the polymerase chain reaction. J Bone Miner Res. 1991;6:1243-1248.
49. Siris ES, Ottman R, Flaster E, Kelsey JL. Familial aggregation of Paget's disease of bone. J Bone Miner Res. 1991; 6:495-500.
50. Cody JD, Singer FR, Roodman GD, et al. Genetic linkage of Paget disease of the bone to chromosome 18q. Am J Hum Genet. 1997;61:1117-1122.
51. Fotino M, Haymovits A, Falk CT. Evidence for linkage between HLA and Paget's disease. Transplant Proc. 1977; 9:1867-1868.
52. Haslam SI, Van Hul W, Morales-Piga A, et al. Paget's disease of bone: evidence for a susceptibility locus on chromosome 18q and for genetic heterogeneity. J Bone Miner Res. 1998;13:911-917.
53. Tilyard MW, Gardner RJ, Milligan L, Cleary TA, Stewart RD. A probable linkage between familial Paget's disease and the HLA loci. Aust N Z J Med. 1982;12:498-500.
54. Breanndan Moore S, Hoffman DL. Absence of HLA linkage in a family with osteitis deformans (Paget's disease of bone). Tissue Antigens. 1988;31:69-70.
55. Good D, Busfield F, Duffy D, et al. Familial Paget's disease of bone: nonlinkage to the PDB1 and PDB2 loci on chromosomes 6p and 18q in a large pedigree. J Bone Miner Res. 2001;16:33-38.
56. Hocking L, Slee F, Haslam SI, et al. Familial Paget's disease of bone: patterns of inheritance and frequency of linkage to chromosome 18q. Bone. 2000;26:577-580.
57. Laurin N, Brown JP, Lemainque A, et al. Paget disease of bone: mapping of two loci at 5q35-qter and 5q31. Am J Hum Genet. 2001;69:528-543.
58. Nance MA, Nuttall FQ, Econs MJ, et al. Heterogeneity in Paget disease of the bone. Am J Med Genet. 2000;92:303-307.
59. Hughes AE, Ralston SH, Marken J, et al. Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet. 2000;24:45-48.
60. Johnson-Pais TL, Singer FR, Bone HG, McMurray CT, Hansen MF, Leach RJ. 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. 2003;18:376-380.
61. Nakatsuka K, Nishizawa Y, Ralston SH. Phenotypic characterization of early onset Paget's disease of bone caused by a 27-bp duplication in theTNFRSF11Agene. J Bone Miner Res. 2003;18:1381-1385.
62. Palenzuela L, Vives-Bauza C, Fernandez-Cadenas I, et al. Familial expansile osteolysis in a large Spanish kindred resulting from an insertion mutation in the TNFRSF11A gene. J Med Genet. 2002;39:E67.
63. Whyte MP, Obrecht SE, Finnegan PM, et al. Osteoprotegerin deficiency and juvenile Paget's disease.NEngl J Med. 2002;347:175-184.
64. Middleton-Hardie C, Zhu Q, Cundy H, et al. Deletion of aspartate 182 in OPG causes juvenile Paget's disease by impairing both protein secretion and binding to RANKL. J Bone Miner Res. 2006;21:438-445.
65. Beyens G, Daroszewska A, de Freitas F, et al. Identification of sex-specific associations between polymorphisms of the osteoprotegerin gene, TNFRSF11B, and Paget's disease of bone. J Bone Miner Res. 2007;22:1062-1071.
66. Chung PY, Beyens G, Riches PL, et al. Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone. J Bone Miner Res. 2010;25:2592-2605.
67. Daroszewska A, Hocking LJ, McGuigan FE, et al. Susceptibility to Paget's disease of bone is influenced by acommon polymorphic variant of osteoprotegerin. J Bone Miner Res. 2004;19:1506-1511.
68. Laurin N, Brown JP, Morissette J, Raymond V. Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet. 2002;70: 1582-1588.
69. Beyens G, Van Hul E, Van Driessche K, et al. Evaluation of the role of the SQSTM1 gene in sporadic Belgian patients with Paget's disease. Calcif Tissue Int. 2004;75:144-152.
70. Collet C, Michou L, Audran M, et al. Paget's disease of bone in the French population: novel SQSTM1 mutations, functional analysis, and genotype-phenotype correlations. J Bone Miner Res. 2007;22:310-317.
71. Cundy T, Naot D, Bava U, Musson D, Tong PC, Bolland M. Familial Paget disease and SQSTM1 mutations in New Zealand. Calcif Tissue Int. 2011;89:258-264.
72. Eekhoff EW, Karperien M, Houtsma D, et al. Familial Paget's disease in The Netherlands: occurrence, identification of new mutations in the sequestosome 1 gene, and their clinical associations. Arthritis Rheum. 2004;50:1650-1654.
73. Falchetti A, Di Stefano M, Marini F, et al. Two novel mutations at exon 8 of the sequestosome 1 (SQSTM1) gene in an Italian series of patients affected by Paget's disease of bone (PDB). J Bone Miner Res. 2004;19:1013-1017.
74. Falchetti A, Di Stefano M, Marini F, et al. Genetic epidemiology of Paget's disease of bone in Italy: sequestosome1/ p62 gene mutational test and haplotype analysis at 5q35 in a large representative series of sporadic and familial Italian cases of Paget's disease of bone. Calcif Tissue Int. 2009; 84:20-37.
75. Good DA, Busfield F, Fletcher BH, et al. Identification of SQSTM1 mutations in familial Paget's disease in Australian pedigrees. Bone. 2004;35:277-282.
76. Hocking LJ, Lucas GJ, Daroszewska A, et al. Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: genotype phenotype correlation, functional analysis, and structural consequences. J Bone Miner Res. 2004;19: 1122-1127.
77. Hocking LJ, Lucas GJ, Daroszewska A, et al. Domainspecific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease.HumMol Genet. 2002; 11:2735-2739.
78. Johnson-Pais TL, Wisdom JH, Weldon KS, et al. Three novel mutations in SQSTM1 identified in familial Paget's disease of bone. J Bone Miner Res. 2003;18:1748-1753.
79. Michou L, Morissette J, Gagnon ER, et al. Novel SQSTM1 mutations in patients with Paget's disease of bone in an unrelated multiethnic American population. Bone. 2011; 48:456-460.
80. Morissette J, Laurin N, Brown JP. Sequestosome 1: mutation frequencies, haplotypes, and phenotypes in familial Paget's disease of bone. J Bone Miner Res. 2006; 21(suppl 2):P38 -P44.
81. Rea SL, Walsh JP, Ward L, et al. 2009 Sequestosome 1 mutations in Paget's disease of bone in Australia: prevalence, genotype/phenotype correlation, and a novel non-UBA domain mutation (P364S) associated with increased NF-κB signaling without loss of ubiquitin binding. J Bone Miner Res. 2009;24:1216-1223.
82. Rea SL, Walsh JP,WardL, et al.Anovel mutation (K378X) in the sequestosome 1 gene associated with increased NF-κB signaling and Paget's disease of bone with a severe phenotype. J Bone Miner Res. 2006;21:1136-1145.
83. Rhodes EC, Johnson-Pais TL, Singer FR, et al. Sequestosome 1 (SQSTM1) mutations in Paget's disease of bone from the United States. Calcif Tissue Int. 2008;82:271-277.
84. Visconti MR, Langston AL, Alonso N, et al. Mutations of SQSTM1 are associated with severity and clinical outcome in Paget disease of bone. J Bone Miner Res. 2010;25:2368-2373.
85. Leach RJ, Singer FR, Ench Y, Wisdom JH, Pina DS, Johnson-Pais TL. Clinical and cellular phenotypes associated with sequestosome 1 (SQSTM1) mutations. J Bone Miner Res. 2006;21(suppl 2):P45-P50.
86. Bolland MJ, Tong PC, Naot D, et al. Delayed development of Paget's disease in offspring inheriting SQSTM1 mutations. J Bone Miner Res. 2007;22:411-415.
87. AlbaghaOM,Visconti MR, Alonso N, et al. Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget's disease of bone. Nat Genet. 2010;42:520-524.
88. Albagha OM, Wani SE, Visconti MR, et al. Genome-wide association identifies three new susceptibility loci for Paget's disease of bone. Nat Genet. 2011;43:685-689.
89. Gianfrancesco F, Rendina D, Di Stefano M, et al. A nonsynonymous TNFRSF11A variation increases NFκB activity and the severity of Paget's disease. J Bone Miner Res. 2012;27:443-452.
90. Del Bo R, Tiloca C, Pensato V, et al. Novel optineurin mutations in patients with familial and sporadic amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2011;82:1239-1243.
91. Iida A, Hosono N, Sano M, et al. Novel deletion mutations ofOPTNin amyotrophic lateral sclerosis in Japanese. Neurobiol Aging. 2012;33:1843.e19-1843.e24.
92. Maruyama H, Morino H, Ito H, et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature. 2010; 465:223-226.
93. Tumer Z, Bertelsen B, Gredal O, et al. Novel heterozygous nonsense mutation of theOPTNgene segregating in a Danish family with ALS. Neurobiol Aging. 2012;33:208. e1-208.e5.
94. van BlitterswijkM,van Vught PW, van EsMA,et al. Novel optineurin mutations in sporadic amyotrophic lateral sclerosis patients. Neurobiol Aging. 2012;33:1016.e1-1016.e7.
95. Fecto F, Yan J, Vemula SP, et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol. 2011;68:1440-1446.
96. Rubino E, Rainero I, Chio A, et al. SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurology. 2012;79:1556-1562.
97. Tucker WS Jr, Hubbard WH, Stryker TD, et al. A new familial disorder of combined lower motor neuron degeneration and skeletal disorganization. Trans AssocAmPhysicians. 1982;95:126-134.
98. Varelas PN, Bertorini TE, Kapaki E, Papageorgiou CT. Paget's disease of bone and motor neuron disease. Muscle Nerve. 1997;20:630.
99. Kovach MJ, Waggoner B, Leal SM, et al. 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. 2001;74:458-475.
100. Lucas GJ, Mehta SG, Hocking LJ, et al. Evaluation of the role of valosin-containing protein in the pathogenesis of familial and sporadic Paget's disease of bone. Bone. 2006; 38:280-285.
101. Mehta SG, Khare M, Ramani R, et al. Genotype-phenotype studies of VCP-associated inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia. Clin Genet. Published Online: August 21, 2012 (doi: 10.1111/cge.12000).
102. Gitcho MA, Strider J, Carter D, et al. VCP mutations causing frontotemporal lobar degeneration disrupt localization of TDP-43 and induce cell death. J Biol Chem. 2009;284: 12384-12398.
103. Braun RJ, Zischka H. Mechanisms of Cdc48/VCP-mediated cell death: from yeast apoptosis to human disease. Biochim Biophys Acta. 2008;1783:1418-1435.
104. Azzam EA, Scott DI, Gregory JS, Mckinnon AD, Helfrich MH. Expression of inclusion body-associated proteins in Paget's disease of bone. Bone. 2009;44:S326.
105. Ju JS, Fuentealba RA, Miller SE, et al. Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J Cell Biol. 2009;187:875-888.
106. Vesa J, Su H, Watts GD, et al. Valosin containing protein associated inclusion body myopathy: abnormal vacuolization, autophagy and cell fusion in myoblasts. Neuromuscul Disord. 2009;19:766-772.
107. Daroszewska A, van't Hof RJ, Rojas JA, et al. A point mutation in the ubiquitin-associated domain of SQSMT1 is sufficient to cause a Paget's disease-like disorder in mice. Hum Mol Genet. 2011;20:2734-2744.
108. Kurihara N, Hiruma Y, Yamana K, et al. Contributions of the measles virus nucleocapsid gene and the SQSTM1/ p62(P392L) mutation to Paget's disease. Cell Metab. 2011; 13:23-34.
109. Kurihara N, Ishizuka S, Demulder A, Menaa C, Roodman GD. Paget's disease-aVDRcoactivator disease? J Steroid Biochem Mol Biol. 2004;89-90:321-325.
110. Kurihara N, Reddy SV, Araki N, et al. Role of TAFII-17, a VDR binding protein, in the increased osteoclast formation in Paget's disease. J Bone Miner Res. 2004;19:1154-1164.
111. Neale SD, Smith R, Wass JA, Athanasou NA. Osteoclast differentiation from circulating mononuclear precursors in Paget's disease is hypersensitive to 1,25-dihydroxyvitamin D(3) and RANKL. Bone. 2000;27:409-416.
112. Roodman GD. Insights into the pathogenesis of Paget's disease. Ann NY Acad Sci. 2010;1192:176-180.
113. Kurihara N, Hiruma Y, Zhou H, et al. Mutation of the sequestosome 1 (p62) gene increases osteoclastogenesis but does not induce Paget disease. J Clin Invest. 2007;117: 133-142.
114. Solomon LR. Billiard-player's fingers: an unusual case of Paget's disease of bone. Br Med J. 1979;1:931.
115. Lever JH. Paget's disease of bone in Lancashire and arsenic pesticide in cotton mill wastewater: a speculative hypothesis. Bone. 2002;31:434-436.
116. Michou L, Collet C, Morissette J, et al. Epidemiogenetic study of French families with Paget's disease of bone. Joint Bone Spine. 2012;79:393-398.
117. Kular J, Tickner J, Chim SM, Xu J. An overview of the regulation of bone remodelling at the cellular level. Clin Biochem. 2012;45:863-873.
118. Lee ZH, Kim HH. Signal transduction by receptor activator of nuclear factor κB in osteoclasts. Biochem Biophys Res Commun. 2003;305:211-214.
119. Boyce BF, Yamashita T, Yao Z, Zhang Q, Li F, Xing L. Roles for NF-κB and c-Fos in osteoclasts. J Bone Miner Metab. 2005;23(suppl):11-15.
120. Franzoso G, Carlson L, Xing L, et al. Requirement for NF-κB in osteoclast and B-cell development. Genes Dev. 1997;11:3482-3496.
121. Iotsova V, Caamano J, Loy J, Yang Y, Lewin A, Bravo R. Osteopetrosis in mice lacking NF-κB1 and NF-κB2. Nat Med. 1997;3:1285-1289.
122. Grigoriadis AE,WangZQ,CecchiniMG,et al. c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science. 1994;266:443-448.
123. Wang ZQ, Ovitt C, Grigoriadis AE, Mohle-Steinlein U, Ruther U, Wagner EF. Bone and haematopoietic defects in mice lacking c-fos. Nature. 1992;360:741-745.
124. Lomaga MA, Yeh WC, Sarosi I, et al. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 1999;13:1015-1024.
125. Naito A, Azuma S, Tanaka S, et al. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells. 1999;4: 353-362.
126. Duran A, Serrano M, Leitges M, et al. The atypical PKCinteracting protein p62 is an important mediator of RANK-activated osteoclastogenesis. Dev Cell. 2004;6: 303-309.
127. Li J, Sarosi I, Yan XQ, et al. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA. 2000;97:1566-1571.
128. Seibenhener ML, Geetha T, Wooten MW. Sequestosome 1/p62-more than just a scaffold. FEBS Lett. 2007;581: 175-179.
129. Long J, Garner TP, Pandya MJ, et al. Dimerisation of the UBA domain of p62 inhibits ubiquitin binding and regulates NF-κB signalling. J Mol Biol. 2010;396:178-194.
130. Moscat J, Diaz-Meco MT, Wooten MW. Signal integration and diversification through the p62 scaffold protein. Trends Biochem Sci. 2007;32:95-100.
131. Lallena MJ, Diaz-Meco MT, Bren G, Paya CV, Moscat J. Activation of IκB kinase β by protein kinase C isoforms. Mol Cell Biol. 1999;19:2180-2188.
132. Sanz L, Diaz-MecoMT,Nakano H, Moscat J. The atypical PKC-interacting protein p62 channels NF-κBactivation by the IL-1-TRAF6 pathway.EMBOJ. 2000;19:1576-1586.
133. Feng Y, Longmore GD. The LIM protein Ajuba influences interleukin-1-induced NF-κB activation by affecting the assembly and activity of the protein kinase Czeta/p62/ TRAF6 signaling complex. Mol Cell Biol. 2005;25:4010-4022.
134. Sanz L, Sanchez P, Lallena MJ, Diaz-Meco MT, Moscat J. The interaction of p62 with RIP links the atypical PKCs to NF-κB activation. EMBO J. 1999;18:3044-3053.
135. Najat D, Garner T, Hagen T, et al. Characterization of a non-UBA domain missense mutation of sequestosome 1(SQSTM1) in Paget's disease of bone. J Bone Miner Res. 2009;24:632-642.
136. Yip KH, Feng H, Pavlos NJ, Zheng MH, Xu J. p62 Ubiquitin binding-associated domain mediated the receptor activator of nuclear factor-κB ligand-induced osteoclast formation: a new insight into the pathogenesis of Paget's disease of bone. Am J Pathol. 2006;169:503-514.
137. Jin W, Chang M, Paul EM, et al. Deubiquitinating enzyme CYLDnegatively regulatesRANKsignaling and osteoclastogenesis in mice. J Clin Invest. 2008;118:1858-1866.
138. Wooten MW, Geetha T, Babu JR, et al. Essential role of sequestosome 1/p62 in regulating accumulation of Lys63-ubiquitinated proteins. J Biol Chem. 2008;283:6783-6789.
139. Kim JY, Ozato K. The sequestosome 1/p62 attenuates cytokine gene expression in activated macrophages by inhibiting IFN regulatory factor 8 and TNF receptor-associated factor 6/NF-κB activity. J Immunol. 2009;182:2131-2140.
140. Ang E, Pavlos NJ, Rea SL, et al. Proteasome inhibitors impair RANKL-induced NF-κB activity in osteoclast-like cells via disruption of p62, TRAF6, CYLD, and IκBα signaling cascades. J Cell Physiol. 2009;220:450-459.
141. Brummelkamp TR, Nijman SM, Dirac AM, Bernards R. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB. Nature. 2003;424:797-801.
142. Kovalenko A, Chable-Bessia C, Cantarella G, Israel A, Wallach D, Courtois G. The tumour suppressor CYLD negatively regulates NF-κB signalling by deubiquitination. Nature. 2003;424:801-805.
143. Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G. CYLD is a deubiquitinating enzyme that negatively regulates NF-κB activation by TNFR family members. Nature. 2003;424:793-796.
144. Wright A, ReileyWW,Chang M, et al. Regulation of early wave of germ cell apoptosis and spermatogenesis by deubiquitinating enzyme CYLD. Dev Cell. 2007;13:705-716.
145. Reiley WW, Jin W, Lee AJ, et al. Deubiquitinating enzyme CYLDnegatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. J Exp Med. 2007;204:1475-1485.
146. Reiley W, Zhang M,WuX, Granger E, Sun SC. Regulation of the deubiquitinating enzyme CYLD by IκB kinase γ-dependent phosphorylation. Mol Cell Biol. 2005;25: 3886-3895.
147. Hutti JE, Shen RR, Abbott DW, et al. Phosphorylation of the tumor suppressorCYLDby the breast cancer oncogene IKKε promotes cell transformation. Mol Cell. 2009;34: 461-472.
148. Sundaram K, Shanmugarajan S, Rao DS, Reddy SV. Mutant p62P392L stimulation of osteoclast differentiation in Paget's disease of bone. Endocrinology. 2011;152:4180-4189.
149. Skaug B, Jiang X, Chen ZJ. The role of ubiquitin in NF-κB regulatory pathways. Annu Rev Biochem. 2009;78:769-796.
150. Lamothe B, Besse A, Campos AD, Webster WK, Wu H, Darnay BG. Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of IκB kinase activation. J Biol Chem. 2007;282:4102-4112.
151. Walsh MC, Kim GK, Maurizio PL, Molnar EE, Choi Y. TRAF6 autoubiquitination-independent activation of the NFκB and MAPK pathways in response to IL-1 and RANKL. PLoS One. 2008;3:e4064.
152. Lamothe B, Campos AD, Webster WK, Gopinathan A, Hur L, Darnay BG. The RING domain and first zinc finger of TRAF6 coordinate signaling by interleukin-1, lipopolysaccharide, and RANKL. J Biol Chem. 2008;283:24871-24880.
153. Megas C, Hatzivassiliou EG, Yin Q, et al. Mutational analysis of TRAF6 reveals a conserved functional role of the RING dimerization interface and a potentially necessary but insufficient role of RING-dependent TRAF6 polyubiquitination towards NF-κBactivation. Cell Signal. 2011; 23:772-777.
154. Takayanagi H, Ogasawara K, Hida S, et al. T-cell-mediated regulation of osteoclastogenesis by signalling crosstalk between RANKL and IFN-γ. Nature. 2000;408:600-605.
155. Wooten MW, Geetha T, Seibenhener ML, Babu JR, Diaz-Meco MT, Moscat J. The p62 scaffold regulates nerve growth factor-induced NF-κB activation by influencing TRAF6 polyubiquitination. J Biol Chem. 2005;280: 35625-35629.
156. Mossetti G, Rendina D, De Filippo G, et al. Interleukin-6 and osteoprotegerin systems in Paget's disease of bone: relationship to risedronate treatment. Bone. 2005;36: 549-554.
157. Ehrlich LA, Roodman GD. The role of immune cells and inflammatory cytokines in Paget's disease and multiple myeloma. Immunol Rev. 2005;208:252-266.
158. Hoyland JA, Freemont AJ, Sharpe PT. Interleukin-6, IL-6 receptor, and IL-6 nuclear factor gene expression in Paget's disease. J Bone Miner Res. 1994;9:75-80.
159. Neale SD, Schulze E, Smith R, Athanasou NA. The influence of serum cytokines and growth factors on osteoclast formation in Paget's disease. QJM. 2002;95:233-240.
160. Roodman GD, Kurihara N, Ohsaki Y, et al. Interleukin 6. A potential autocrine/paracrine factor in Paget's disease of bone. J Clin Invest. 1992;89:46-52.
161. Wild P, Farhan H, McEwan DG, et al. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science. 2011;333:228-233.
162. Kirkin V, Lamark T, Johansen T, Dikic I. NBR1 cooperates with p62 in selective autophagy of ubiquitinated targets. Autophagy. 2009;5:732-733.
163. Kirkin V, Lamark T, Sou YS, et al. A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol Cell. 2009;33:505-516.
164. Lamark T, Kirkin V, Dikic I, Johansen T. NBR1 and p62 as cargo receptors for selective autophagy of ubiquitinated targets. Cell Cycle. 2009;8:1986-1990.
165. von Muhlinen N, Thurston T, Ryzhakov G, Bloor S, Randow F. NDP52, a novel autophagy receptor for ubiquitin-decorated cytosolic bacteria. Autophagy. 2010;6: 288-289.
166. Fujita K, Srinivasula SM. TLR4-mediated autophagy in macrophages is a p62-dependent type of selective autophagy of aggresome-like induced structures (ALIS). Autophagy. 2011;7:552-554.
167. Into T, Inomata M, Niida S, Murakami Y, Shibata K. Regulation of MyD88 aggregation and the MyD88-dependent signaling pathway by sequestosome 1 and histone deacetylase 6. J Biol Chem. 2010;285:35759-35769.
168. Inomata M, Niida S, Shibata K, Into T. Regulation of Tolllike receptor signaling by NDP52-mediated selective autophagy is normally inactivated by A20. Cell Mol Life Sci. 2012;69:963-979.
169. Lamark T, Johansen T. 2012 Aggrephagy: selective disposal of protein aggregates by macroautophagy. Int J Cell Biol. 2012;736905.
170. Into T, Inomata M, Takayama E, Takigawa T. Autophagy in regulation of Toll-like receptor signaling. Cell Signal. 2012;24:1150-1162.
171. Cavey JR, Ralston SH, Hocking LJ, et al. Loss of ubiquitinbinding associated with Paget's disease of bone p62 (SQSTM1) mutations. J Bone Miner Res. 2005;20:619-624.
172. Garner TP, Long J, Layfield R, Searle MS. Impact of p62/ SQSTM1 UBA domain mutations linked to Paget's disease of bone on ubiquitin recognition. Biochemistry. 2011;50: 4665-4674.
173. Heinen C, Garner TP, Long J, et al. Mutant p62/SQSTM1 UBA domains linked to Paget's disease of bone differ in their abilities to function as stabilization signals. FEBS Lett. 2010;584:1585-1590.
174. Matsumoto G, Wada K, Okuno M, Kurosawa M, Nukina N. Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol Cell. 2011;44:279-289.
175. Darnay BG, Ni J, Moore PA, Aggarwal BB. Activation of NF-κB by RANK requires tumor necrosis factor receptorassociated factor (TRAF) 6 and NF-κB-inducing kinase. Identification of a novel TRAF6 interaction motif. J Biol Chem. 1999;274:7724-7731.
176. Theoleyre S, Wittrant Y, Tat SK, Fortun Y, Redini F, Heymann D. The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev. 2004;15:457-475.
177. Matsumoto M, Sudo T, Maruyama M, Osada H, Tsujimoto M. Activation of p38 mitogen-activated protein kinase is crucial in osteoclastogenesis induced by tumor necrosis factor. FEBS Lett. 2000;486:23-28.
178. Matsumoto M, Sudo T, Saito T, Osada H, Tsujimoto M. Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-κB ligand (RANKL). J Biol Chem. 2000; 275:31155-31161.
179. Kawai K, Saito A, Sudo T, Osada H. Specific regulation of cytokine-dependent p38 MAP kinase activation by p62/ SQSTM1. J Biochem. 2008;143:765-772.
180. Sudo T, Maruyama M, Osada H. p62 Functions as a p38 MAP kinase regulator. Biochem Biophys Res Commun. 2000;269:521-525.
181. Cano E, Mahadevan LC. Parallel signal processing among mammalian MAPKs. Trends Biochem Sci. 1995;20:117-122.
182. Hodge JM, Collier FM, Pavlos NJ, Kirkland MA, Nicholson GC. M-CSF potently augments RANKL-induced resorption activation in mature human osteoclasts. PLoS One. 2011;6:e21462.
183. Miyazaki T, Katagiri H, Kanegae Y, et al. Reciprocal role of ERK and NF-κB pathways in survival and activation of osteoclasts. J Cell Biol. 2000;148:333-342.
184. Feng Y, Zhao H, Luderer HF, et al. The LIM protein, Limd1, regulates AP-1 activation through an interaction with Traf6 to influence osteoclast development. J Biol Chem. 2007;282:39-48.
185. Rea SL. Functional significance of sequestosome 1 (SQSTM1/ p62) mutations in Paget's disease of bone [PhD thesis]. Cawley, WesternAustralia: Faculty ofMedicineandDentistry, School of Surgery, The University of Western Australia; 2010.
186. Moscat J, Diaz-Meco MT. p62 At the crossroads of autophagy, apoptosis, and cancer. Cell. 2009;137:1001-1004.
187. Ciani B, Layfield R, Cavey JR, Sheppard PW, Searle MS. Structure of the ubiquitin-associated domain of p62 (SQSTM1) and implications for mutations that cause Paget's disease of bone. J Biol Chem. 2003;278:37409-37412.
188. Shin J. P62 and the sequestosome, a novel mechanism for protein metabolism. Arch Pharm Res. 1998;21:629-633.
189. Vadlamudi RK, Joung I, Strominger JL, Shin J. p62, A phosphotyrosine-independent ligand of the SH2 domain of p56lck, belongs to a new class of ubiquitin-binding proteins. J Biol Chem. 1996;271:20235-20237.
190. Martinez A, Portero-OtinM,Pamplona R, Ferrer I. Protein targets of oxidative damage in human neurodegenerative diseases with abnormal protein aggregates. Brain Pathol. 2010;20:281-297.
191. Stumptner C, Fuchsbichler A, Zatloukal K, Denk H. In vitro production of Mallory bodies and intracellular hyaline bodies: the central role of sequestosome 1/p62. Hepatology. 2007;46:851-860.
192. Wooten MW, Hu X, Babu JR, et al. Signaling, polyubiquitination, trafficking, and inclusions: sequestosome 1/p62's role in neurodegenerative disease. J Biomed Biotechnol. 2006;2006:62079.
193. Kuusisto E, Salminen A, Alafuzoff I. Ubiquitin-binding protein p62 is present in neuronal and glial inclusions in human tauopathies and synucleinopathies. Neuroreport. 2001;12:2085-2090.
194. Settembre C, Fraldi A, Rubinsztein DC, Ballabio A. Lysosomal storage diseases as disorders of autophagy. Autophagy. 2008;4:113-114.
195. Strnad P, Zatloukal K, Stumptner C, Kulaksiz H, Denk H. Mallory-Denk-bodies: lessons from keratin-containing hepatic inclusion bodies. Biochim Biophys Acta. 2008;1782: 764-774.
196. Zatloukal K, Stumptner C, Fuchsbichler A, et al. p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases. Am J Pathol. 2002;160:255-263.
197. Geetha T, Vishwaprakash N, Sycheva M, Babu JR. Sequestosome 1/p62: across diseases. Biomarkers. 2012;17: 99-103.
198. Inoue D, Suzuki T, Mitsuishi Y, et al. Accumulation of p62/SQSTM1 is associated with poor prognosis in patients with lung adenocarcinoma. Cancer Sci. 2012;103:760-766.
199. Komatsu M. Potential role of p62 in tumor development. Autophagy. 2011;7:1088-1090.
200. Rolland P, Madjd Z, Durrant L, Ellis IO, Layfield R, Spendlove I. The ubiquitin-binding protein p62 is expressed in breast cancers showing features of aggressive disease. Endocr Relat Cancer. 2007;14:73-80.
201. Thompson HG, Harris JW, Wold BJ, Lin F, Brody JP. p62 Overexpression in breast tumors and regulation by prostate-derived Ets factor in breast cancer cells. Oncogene. 2003;22:2322-2333.
202. Stumptner C, Fuchsbichler A, Heid H, Zatloukal K, Denk H. Mallory body-a disease-associated type of sequestosome. Hepatology. 2002;35:1053-1062.
203. Babu JR, Geetha T, Wooten MW. Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J Neurochem. 2005;94:192-203.
204. Bjorkoy G, Lamark T, Brech A, et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol. 2005;171:603-614.
205. Bjorkoy G, Lamark T, Pankiv S, Overvatn A, Brech A, Johansen T. Monitoring autophagic degradation of p62/ SQSTM1. Methods Enzymol. 2009;452:181-197.
206. Komatsu M, Waguri S, Koike M, et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell. 2007;131:1149-1163.
207. Christian F, Anthony DF, Vadrevu S, et al. p62 (SQSTM1) and cyclic AMP phosphodiesterase-4A4 (PDE4A4) locate to a novel, reversible protein aggregate with links to autophagy and proteasome degradation pathways. Cell Signal. 2010;22:1576-1596.
208. Houslay MD, Christian F. p62 (SQSTM1) forms part of a novel, reversible aggregate containing a specific conformer of the cAMP degrading phosphodiesterase, PDE4A4. Autophagy. 2010;6:1198-1200.
209. Layfield R, Hocking LJ. SQSTM1 and Paget's disease of bone. Calcif Tissue Int. 2004;75:347-357.
210. Mueller TD, Kamionka M, Feigon J. Specificity of the interaction between ubiquitin-associated domains and ubiquitin. J Biol Chem. 2004;279:11926-11936.
211. Jensen LE, Whitehead AS. Ubiquitin activated tumor necrosis factor receptor associated factor-6 (TRAF6) is recycled via deubiquitination. FEBS Lett. 2003;553:190-194.
212. Reddy SV, Menaa C, Singer FR, Demulder A, Roodman GD. Cell biology of Paget's disease. J Bone Miner Res. 1999;14(suppl 2):3-8.
213. Pankiv S, Lamark T, Bruun JA, Overvatn A, Bjorkoy G, Johansen T. Nucleocytoplasmic shuttling ofp62/SQSTM1 and its role in recruitment of nuclear polyubiquitinated proteins to promyelocytic leukemia bodies. J Biol Chem. 2010;285:5941-5953.
214. Ichimura Y, Komatsu M. Selective degradation of p62 by autophagy. Semin Immunopathol. 2010;32:431-436.
215. Seibenhener ML, Babu JR, Geetha T, Wong HC, Krishna NR, Wooten MW. Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol Cell Biol. 2004;24:8055-8068.
216. Buchberger A. From UBA to UBX: new words in the ubiquitin vocabulary. Trends Cell Biol. 2002;12:216-221.
217. Geetha T, Seibenhener ML, Chen L, Madura K, Wooten MW. p62 Serves as a shuttling factor for TrkA interaction with the proteasome. Biochem Biophys Res Commun. 2008;374:33-37.
218. Ramesh Babu J, Lamar Seibenhener M, Peng J, et al. Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration. J Neurochem. 2008;106:107-120.
219. Eskelinen EL. The dual role of autophagy in cancer. Curr Opin Pharmacol. 2011;11:294-300.
220. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132:27-42.
221. McPhee CK, Baehrecke EH. The engulfment receptor Draper is required for autophagy during cell death. Autophagy. 2010;6:1192-1193.
222. Rabinowitz JD, White E. Autophagy and metabolism. Science. 2010;330:1344-1348.
223. Kim PK, Hailey DW, Mullen RT, Lippincott-Schwartz J. Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes. Proc Natl Acad Sci USA. 2008; 105:20567-20574.
224. Pankiv S, Clausen TH, Lamark T, et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 2007;282:24131-24145.
225. Nagaoka U, Kim K, Jana NR, et al. Increased expression of p62 in expanded polyglutamine-expressing cells and its association with polyglutamine inclusions. J Neurochem. 2004;91:57-68.
226. Gal J, Strom AL, Kilty R, Zhang F, Zhu H. p62 Accumulates and enhances aggregate formation in model systems of familial amyotrophic lateral sclerosis. J Biol Chem. 2007;282:11068-11077.
227. Gal J, Strom AL, Kwinter DM, et al. Sequestosome 1/p62 links familial ALS mutant SOD1 to LC3 via an ubiquitinindependent mechanism. J Neurochem. 2009;111:1062-1073.
228. Hocking LJ, Whitehouse C, Helfrich MH. Autophagy: a new player in skeletal maintenance? J Bone Miner Res. 2012;27:1439-1447.
229. DeSelm CJ, Miller BC, Zou W, et al. Autophagy proteins regulate the secretory component of osteoclastic bone resorption. Dev Cell. 2011;21:966-974.
230. Tresse E, Salomons FA, Vesa J, et al. VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD. Autophagy. 2010;6:217-227.
231. Azzam EA, Helfrich MH, Hocking LJ. Paget's diseasecausing mutations in sequestosome-1 impair autophagic degradation. J Bone Miner Res. 2011;26:Abstract 1081.
232. Criollo A, Senovilla L, Authier H, et al. IKK connects autophagy to major stress pathways. Autophagy. 2010;6: 189-191.
233. Criollo A, Senovilla L, Authier H, et al. The IKK complex contributes to the induction of autophagy.EMBOJ. 2010; 29:619-631.
234. Criollo A, Chereau F, Malik SA, et al. Autophagy is required for the activation of NFκB. Cell Cycle. 2012;11: 194-199.
235. Kim JE, You DJ, Lee C, Ahn C, Seong JY, Hwang JI. Suppression of NF-κB signaling by KEAP1 regulation of IKKβ activity through autophagic degradation and inhibition of phosphorylation. Cell Signal. 2010;22:1645-1654.
236. Criollo A, Niso-Santano M, Malik SA, et al. Inhibition of autophagy by TAB2 and TAB3.EMBOJ. 2011;30:4908-4920.
237. Mizukami J, Takaesu G, Akatsuka H, et al. Receptor activator of NF-κB ligand (RANKL) activates TAK1 mitogen-activated protein kinase kinase kinase through a signaling complex containing RANK, TAB2, and TRAF6. Mol Cell Biol. 2002;22:992-1000.
238. Niso-Santano M, Criollo A, Malik SA, et al. Direct molecular interactions between Beclin 1 and the canonical NFκB activation pathway. Autophagy. 2012;8:268-270.
239. Bjorkoy G, Lamark T, Johansen T. p62/SQSTM1: a missing link between protein aggregates and the autophagy machinery. Autophagy. 2006;2:138-139.
240. Nagley P, Higgins GC, Atkin JD, Beart PM. Multifaceted deaths orchestrated by mitochondria in neurones. Biochim Biophys Acta. 2010;1802:167-185.
241. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35:495-516.
242. Schwartzman RA, Cidlowski JA. Apoptosis: the biochemistry and molecular biology of programmed cell death. Endocr Rev. 1993;14:133-151.
243. Jin Z, Li Y, Pitti R, et al. Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. Cell. 2009;137:721-735.
244. Picarda G, Trichet V, Teletchea S, Heymann D, Redini F. TRAIL receptor signaling and therapeutic option in bone tumors: the trap of the bone microenvironment.AmJ Cancer Res. 2012;2:45-64.
245. Kuusisto E, Suuronen T, Salminen A. Ubiquitin-binding protein p62 expression is induced during apoptosis and proteasomal inhibition in neuronal cells. Biochem Biophys Res Commun. 2001;280:223-228.
246. Young M, Takahashi Y, Khan O, et al. Autophagosomal membrane serves as a platform for an intracellular deathinducing signaling complex (iDISC)-mediated caspase-8 activation and apoptosis. J Biol Chem. 2012;287:12455-12468.
247. Chamoux E, Couture J, Bisson M, Morissette J, Brown JP, Roux S. The p62 P392L mutation linked to Paget's disease induces activation of human osteoclasts. Mol Endocrinol. 2009;23:1668-1680.
248. Michou L, Chamoux E, Couture J, Morissette J, Brown JP, Roux S. Gene expression profile in osteoclasts from patients with Paget's disease of bone. Bone. 2010;46:598-603.
249. Brandwood CP, Hoyland JA, Hillarby MC, et al. Apoptotic gene expression in Paget's disease: a possible role for Bcl-2. J Pathol. 2003;201:504-512.
250. Xu Y, Morse LR, da Silva RA, et al. PAMM: a redox regulatory protein that modulates osteoclast differentiation. Antioxid Redox Signal. 2010;13:27-37.
251. Kim H, Jung Y, Shin BS, et al. Redox regulation of lipopolysaccharide-mediated sulfiredoxin induction, which depends on both AP-1 and Nrf2. J Biol Chem. 2010;285: 34419-34428.
252. Yip KH, Zheng MH, Steer JH, et al. Thapsigargin modulates osteoclastogenesis through the regulation ofRANKLinduced signaling pathways and reactive oxygen species production. J Bone Miner Res. 2005;20:1462-1471.
253. Komatsu M, Kurokawa H, Waguri S, et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol. 2010;12:213-223.
254. Baird L, Dinkova-Kostova AT. The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol. 2011;85:241-272.
255. Hinoi E, Fujimori S, Wang L, Hojo H, Uno K, Yoneda Y. Nrf2 negatively regulates osteoblast differentiation via interfering with Runx2-dependent transcriptional activation. J Biol Chem. 2006;281:18015-18024.
256. Copple IM, Lister A, Obeng AD, et al. Physical and functional interaction of sequestosome 1 with Keap1 regulates the Keap1-Nrf2 cell defense pathway. J Biol Chem. 2010; 285:16782-16788.
257. Jain A, Lamark T, Sjottem E, et al. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response elementdriven gene transcription. J Biol Chem. 2010;285:22576-22591.
258. Gu JM, Zhang ZL, Zhang H, et al. Thirteen Chinese patients with sporadic Paget's disease of bone: clinical features, SQSTM1 mutation identification, and functional analysis. J Bone Miner Metab. 2012;30:525-533.
259. Davie M, Davies M, Francis R, Fraser W, Hosking D, Tansley R. Paget's disease of bone: a review of 889 patients. Bone. 1999;24:11S-12S.
260. Matthews BG, Naot D, Bava U, et al. Absence of somatic SQSTM1 mutations in Paget's disease of bone. J Clin Endocrinol Metab. 2009;94:691-694.
261. Fan W, Tang Z, Chen D, et al. Keap1 facilitates p62-mediated ubiquitin aggregate clearance via autophagy. Autophagy. 2010;6:614-621.
262. Wright T, Rea SL, Goode A, et al. The S349T mutation of SQSTM1 links Keap1/Nrf2 signalling to Paget's disease of bone. Bone. 2013;52:699-706.