Calcified Tissue International

, Volume 91, Issue 2, pp 97–113 | Cite as

Pathogenesis of Paget Disease of Bone

  • Stuart H. Ralston
  • Rob Layfield


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.


Paget disease of bone Osteoclast Cartilage 



Stuart H. Ralston has a consultant/advisory role to Novartis, Merck, and Eli Lilly.

Conflict of interest: Rob Layfield has stated that he has no conflict of interest.


  1. 1.
    Kanis JA (1992) Pathophysiology and treatment of Paget’s disease of bone. Martin Dunitz, LondonGoogle Scholar
  2. 2.
    Meunier PJ, Coindre JM, Edouard CM, Arlot ME (1980) Bone histomorphometry in Paget’s disease. Quantitative and dynamic analysis of pagetic and nonpagetic bone tissue. Arthritis Rheum 23:1095–1103PubMedCrossRefGoogle Scholar
  3. 3.
    Chamoux E, Couture J, Bisson M, Morissette J, Brown JP, Roux S (2009) The p62 P392L mutation linked to Paget’s disease induces activation of human osteoclasts. Mol Endocrinol 23:1668–1680PubMedCrossRefGoogle Scholar
  4. 4.
    Albagha OME, Wani S, Visconti MR, Alonso N, Goodman K, Cundy T, Brandi ML, Chung PY, Dargie R, Devogelaer JP, Falchetti A, Fraser WD, Gennari L, Gianfrancesco F, Hooper MJ, Van Hul W, Isaia G, Nicholson GC, Nuti R, Del Pino MJ, Ratajczak T, Rea SL, Rendina D, Gonzalez-Sarmiento R, Di SM, Ward L, Walsh JP, Ralston SH (2011) Genome-wide association identifies three new susceptibility loci for Paget’s disease of bone. Nat Genet 43:685–689PubMedCrossRefGoogle Scholar
  5. 5.
    Ralston SH (2008) Pathogenesis of Paget’s disease of bone. Bone 43:819–825PubMedCrossRefGoogle Scholar
  6. 6.
    Barker DJ (1984) The epidemiology of Paget’s disease of bone. Br Med Bull 40:396–400PubMedGoogle Scholar
  7. 7.
    Detheridge FM, Guyer PB, Barker DJ (1982) European distribution of Paget’s disease of bone. Br Med J 285:1005–1008CrossRefGoogle Scholar
  8. 8.
    van Staa TP, Selby P, Leufkens HG, Lyles K, Sprafka JM, Cooper C (2002) Incidence and natural history of Paget’s disease of bone in England and Wales. J Bone Miner Res 17:465–471PubMedCrossRefGoogle Scholar
  9. 9.
    Takata S, Hashimoto J, Nakatsuka K, Yoshimura N, Yoh K, Ohno I, Yabe H, Abe S, Fukunaga M, Terada M, Zamma M, Ralston SH, Morii H, Yoshikawa H (2006) Guidelines for diagnosis and management of Paget’s disease of bone in Japan. J Bone Miner Metab 24:359–367PubMedCrossRefGoogle Scholar
  10. 10.
    Mays S (2010) Archaeological skeletons support a northwest European origin for Paget’s disease of bone. J Bone Miner Res 25:1839–1841PubMedCrossRefGoogle Scholar
  11. 11.
    Lucas GJ, Hocking LJ, Daroszewska A, Cundy T, Nicholson GC, Walsh JP, Fraser WD, Meier C, Hooper MJ, Ralston SH (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 20:227–231PubMedCrossRefGoogle Scholar
  12. 12.
    Falchetti A, Di Stefano M, Marini F, Ortolani S, Ulivieri MF, Bergui S, Masi L, Cepollaro C, Benucci M, Di Munno O, Rossini M, Adami S, Del Puente A, Isaia G, Torricelli F, Brandi ML (2009) 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 84:20–37PubMedCrossRefGoogle Scholar
  13. 13.
    Doyle T, Gunn J, Anderson G, Gill M, Cundy T (2002) Paget’s disease in New Zealand: evidence for declining prevalence. Bone 31:616–619PubMedCrossRefGoogle Scholar
  14. 14.
    Poor G, Donath J, Fornet B, Cooper C (2006) Epidemiology of Paget’s disease in Europe: the prevalence is decreasing. J Bone Miner Res 21:1545–1549PubMedCrossRefGoogle Scholar
  15. 15.
    Cundy HR, Gamble G, Wattie D, Rutland M, Cundy T (2004) Paget’s disease of bone in New Zealand: continued decline in disease severity. Calcif Tissue Int 75:358–364PubMedCrossRefGoogle Scholar
  16. 16.
    Gennari L, Gianfrancesco F, Di Stefano M, Rendina D, Merlotti D, Esposito T, Gallone S, Fusco P, Rainero I, Fenoglio P, Mancini M, Martini G, Bergui S, De Filippo G, Isaia G, Strazzullo P, Nuti R, Mossetti G (2010) SQSTM1 gene analysis and gene–environment interaction in Paget’s disease of bone. J Bone Miner Res 25:1375–1384PubMedCrossRefGoogle Scholar
  17. 17.
    Martini G, Gennari L, Merlotti D, Salvadori S, Franci MB, Campagna S, Avanzati A, De Paola V, Valleggi F, Nuti R (2007) Serum OPG and RANKL levels before and after intravenous bisphosphonate treatment in Paget’s disease of bone. Bone 40:457–463PubMedCrossRefGoogle Scholar
  18. 18.
    Gennari L, Di Stefano M, Merlotti D, Giordano N, Martini G, Tamone C, Zatteri R, De Lucchi R, Baldi C, Vattimo A, Capoccia S, Burroni L, Geraci S, De Paola V, Calabro A, Avanzati A, Isaia G, Nuti R (2005) Prevalence of Paget’s disease of bone in Italy. J Bone Miner Res 20:1845–1850PubMedCrossRefGoogle Scholar
  19. 19.
    Tiegs RD, Lohse CM, Wollan PC, Melton LJ (2000) Long-term trends in the incidence of Paget’s disease of bone. Bone 27:423–427PubMedCrossRefGoogle Scholar
  20. 20.
    Siris ES (1994) Epidemiological aspects of Paget’s disease: family history and relationship to other medical conditions. Semin Arthritis Rheum 23:222–225PubMedCrossRefGoogle Scholar
  21. 21.
    Barker DJ, Gardner MJ (1974) Distribution of Paget’s diease in England, Wales and Scotland and a possible relationship with vitamin D deficiency in childhood. Br J Prev Soc Med 28:226–232PubMedGoogle Scholar
  22. 22.
    Lever JH (2002) Paget’s disease of bone in Lancashire and arsenic pesticide in cotton mill wastewater: a speculative hypothesis. Bone 31:434–436PubMedCrossRefGoogle Scholar
  23. 23.
    Solomon LR (1979) Billiard-player’s fingers: an unusual case of Paget’s disease of bone. Br Med J 1:931PubMedCrossRefGoogle Scholar
  24. 24.
    Gasper TM (1979) Paget’s disease in a treadle machine operator [letter]. Br Med J 1:1217–1218PubMedCrossRefGoogle Scholar
  25. 25.
    Merlotti D, Gennari L, Galli B, Martini G, Calabro A, De Paola V, Ceccarelli E, Nardi P, Avanzati A, Nuti R (2005) Characteristics and familial aggregation of Paget’s disease of bone in Italy. J Bone Miner Res 20:1356–1364PubMedCrossRefGoogle Scholar
  26. 26.
    Lopez-Abente G, Morales-Piga A, Elena-Ibanez A, Rey–Rey JS, Corres-Gonzalez J (1997) Cattle, pets, and Paget’s disease of bone. Epidemiology 8:247–251PubMedCrossRefGoogle Scholar
  27. 27.
    Rebel A, Malkani K, Basle M, Bregeon C, Patezour A, Filmon R (1974) Ultrastructural characteristics of osteoclasts in Paget’s disease. Rev Rhum Mal Osteoartic 41:767–771PubMedGoogle Scholar
  28. 28.
    Mills BG, Singer FR, Weiner LP, Suffin SC, Stabile E, Holst P (1984) Evidence for both respiratory syncytial virus and measles virus antigens in the osteoclasts of patients with Paget’s disease of bone. Clin Orthop Relat Res 183:303–311PubMedGoogle Scholar
  29. 29.
    O’Driscoll JB, Anderson DC (1985) Past pets and Paget’s disease. Lancet 2:919–921PubMedCrossRefGoogle Scholar
  30. 30.
    Ralston SH, Afzal MA, Helfrich MH, Fraser WD, Gallagher JA, Mee A, Rima B (2007) Multicenter blinded analysis of RT-PCR detection methods for paramyxoviruses in relation to Paget’s disease of bone. J Bone Miner Res 22:569–577PubMedCrossRefGoogle Scholar
  31. 31.
    Rima BK, Gassen U, Helfrich MH, Ralston SH (2002) The pro and con of measles virus in Paget’s disease: con. J Bone Miner Res 17:2290–2292PubMedCrossRefGoogle Scholar
  32. 32.
    Friedrichs WE, Reddy SV, Singer FR, Roodman GD (2002) The pro and con of measles virus in Paget’s disease: pro. J Bone Miner Res 17:2293CrossRefGoogle Scholar
  33. 33.
    Langston AL, Campbell MK, Fraser WD, MacLennan GS, Selby PL, Ralston SH (2010) Randomised trial of intensive bisphosphonate treatment versus symptomatic management in Paget’s disease of bone. J Bone Miner Res 25:20–31PubMedCrossRefGoogle Scholar
  34. 34.
    Langston AL, Campbell MK, Fraser WD, Maclennan G, Selby P, Ralston SH (2007) Clinical determinants of quality of life in Paget’s disease of bone. Calcif Tissue Int 80:1–9PubMedCrossRefGoogle Scholar
  35. 35.
    Mills BG, Yabe H, Singer FR (1988) Osteoclasts in human osteopetrosis contain viral-nucleocapsid-like nuclear inclusions. J Bone Miner Res 3:101–106PubMedCrossRefGoogle Scholar
  36. 36.
    Bianco P, Silvestrini G, Ballanti P, Bonucci E (1992) Paramyxovirus-like nuclear inclusions identical to those of Paget’s disease of bone detected in giant cells of primary oxalosis. Virchows Arch Pathol Anat Histopathol 421:427–433CrossRefGoogle Scholar
  37. 37.
    Helfrich MH, Hobson RP, Grabowski PS, Zurbriggen A, Cosby SL, Dickson GR, Fraser WD, Ooi CG, Selby PL, Crisp AJ, Wallace RG, Kahn S, Ralston SH (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 15:2315–2329PubMedCrossRefGoogle Scholar
  38. 38.
    Sieradzan KA, Mechan AO, Jones L, Wanker EE, Nukina N, Mann DM (1999) Huntington’s disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein. Exp Neurol 156:92–99PubMedCrossRefGoogle Scholar
  39. 39.
    Daroszewska A, van’t Hof RJ, Rojas JA, Layfield R, Landao-Basonga E, Rose L, Rose K, Ralston SH (2011) 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 20:2734–2744PubMedCrossRefGoogle Scholar
  40. 40.
    Neale SD, Smith R, Wass JA, Athanasou NA (2000) Osteoclast differentiation from circulating mononuclear precursors in Paget’s disease is hypersensitive to 1,25-dihydroxyvitamin D3 and RANKL. Bone 27:409–416PubMedCrossRefGoogle Scholar
  41. 41.
    Roodman GD, Kurihara N, Ohsaki Y, Kukita A, Hosking D, Demulder A, Smith JF, Singer FR (1992) Interleukin 6. A potential autocrine/paracrine factor in Paget’s disease of bone. J Clin Invest 89:46–52PubMedCrossRefGoogle Scholar
  42. 42.
    Natale VM, Filho WJ, Duarte AJ (1997) Cellular immunity aspects in elderly subjects with Paget’s disease of bone. Calcif Tissue Int 60:410–414PubMedCrossRefGoogle Scholar
  43. 43.
    Ralston SH, Hoey SA, Gallacher SJ, Adamson BB, Boyle IT (1994) Cytokine and growth factor expression in Paget’s disease: analysis by reverse-transcription/polymerase chain reaction. Br J Rheumatol 33:620–625PubMedCrossRefGoogle Scholar
  44. 44.
    Nagy ZB, Gergely P, Donath J, Borgulya G, Csanad M, Poor G (2008) Gene expression profiling in Paget’s disease of bone: upregulation of interferon signaling pathways in pagetic monocytes and lymphocytes. J Bone Miner Res 23:253–259PubMedCrossRefGoogle Scholar
  45. 45.
    Takayanagi H, Kim S, Matsuo K, Suzuki H, Suzuki T, Sato K, Yokochi T, Oda H, Nakamura K, Ida N, Wagner EF, Taniguchi T (2002) RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta. Nature 416:744–749PubMedCrossRefGoogle Scholar
  46. 46.
    Matsumoto M, Sudo T, Saito T, Osada H, Tsujimoto M (2000) Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-kappa B ligand (RANKL). J Biol Chem 275:31155–31161PubMedCrossRefGoogle Scholar
  47. 47.
    Sundaram K, Senn J, Yuvaraj S, Rao DS, Reddy SV (2009) FGF-2 stimulation of RANK ligand expression in Paget’s disease of bone. Mol Endocrinol 23:1445–1454PubMedCrossRefGoogle Scholar
  48. 48.
    Neale SD, Schulze E, Smith R, Athanasou NA (2002) The influence of serum cytokines and growth factors on osteoclast formation in Paget’s disease. QJM 95:233–240PubMedCrossRefGoogle Scholar
  49. 49.
    Albagha OM, Visconti MR, Alonso N, Langston AL, Cundy T, Dargie R, Dunlop MG, Fraser WD, Hooper MJ, Isaia G, Nicholson GC, Del Pino MJ, Gonzalez-Sarmiento R, Di Stefano M, Tenesa A, Walsh JP, Ralston SH (2010) Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget’s disease of bone. Nat Genet 42:520–524PubMedCrossRefGoogle Scholar
  50. 50.
    McCarthy HS, Marshall MJ (2010) Dickkopf-1 as a potential therapeutic target in Paget’s disease of bone. Expert Opin Ther Targets 14:221–230PubMedCrossRefGoogle Scholar
  51. 51.
    Duran A, Serrano M, Leitges M, Flores JM, Picard S, Brown JP, Moscat J, Diaz-Meco MT (2004) The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis. Dev Cell 6:303–309PubMedCrossRefGoogle Scholar
  52. 52.
    Rea SL, Walsh JP, Ward L, Yip K, Ward BK, Kent GN, Steer JH, Xu J, Ratajczak T (2006) A novel mutation (K378X) in the sequestosome 1 gene associated with increased NF-kappaB signaling and Paget’s disease of bone with a severe phenotype. J Bone Miner Res 21:1136–1145PubMedCrossRefGoogle Scholar
  53. 53.
    Jin W, Chang M, Paul EM, Babu G, Lee AJ, Reiley W, Wright A, Zhang M, You J, Sun SC (2008) Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice. J Clin Invest 118:1858–1866PubMedCrossRefGoogle Scholar
  54. 54.
    Sundaram K, Shanmugarajan S, Rao DS, Reddy SV (2011) Mutant p62P392L stimulation of osteoclast differentiation in Paget’s disease of bone. Endocrinology 152:4180–4189PubMedCrossRefGoogle Scholar
  55. 55.
    Demulder A, Takahashi S, Singer FR, Hosking DJ, Roodman GD (1993) Abnormalities in osteoclast precursors and marrow accessory cells in Paget’s disease. Endocrinology 133:1978–1982PubMedCrossRefGoogle Scholar
  56. 56.
    Sun SG, Lau YS, Itonaga I, Sabokbar A, Athanasou NA (2006) Bone stromal cells in pagetic bone and Paget’s sarcoma express RANKL and support human osteoclast formation. J Pathol 209:114–120PubMedCrossRefGoogle Scholar
  57. 57.
    Naot D, Bava U, Matthews B, Callon KE, Gamble GD, Black M, Song S, Pitto RP, Cundy T, Cornish J, Reid IR (2007) Differential gene expression in cultured osteoblasts and bone marrow stromal cells from patients with Paget’s disease of bone. J Bone Miner Res 22:298–309PubMedCrossRefGoogle Scholar
  58. 58.
    Morales-Piga AA, Rey–Rey JS, Corres-Gonzalez J, Garcia-Sagredo JM, Lopez-Abente G (1995) Frequency and characteristics of familial aggregation of Paget’s disease of bone. J Bone Miner Res 10:663–670PubMedCrossRefGoogle Scholar
  59. 59.
    Morissette J, Laurin N, Brown JP (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
  60. 60.
    Eekhoff EW, Karperien M, Houtsma D, Zwinderman AH, Dragoiescu C, Kneppers AL, Papapoulos SE (2004) Familial Paget’s disease in the Netherlands: occurrence, identification of new mutations in the sequestosome 1 gene, and their clinical associations. Arthritis Rheum 50:1650–1654PubMedCrossRefGoogle Scholar
  61. 61.
    Siris ES, Ottman R, Flaster E, Kelsey JL (1991) Familial aggregation of Paget’s disease of bone. J Bone Miner Res 6:495–500PubMedCrossRefGoogle Scholar
  62. 62.
    Sofaer JA, Holloway SM, Emery AE (1983) A family study of Paget’s disease of bone. J Epidemiol Community Health 37:226–231PubMedCrossRefGoogle Scholar
  63. 63.
    Hocking LJ, Herbert CA, Nicholls RK, Williams F, Bennett ST, Cundy T, Nicholson GC, Wuyts W, Van Hul W, Ralston SH (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 69:1055–1061PubMedCrossRefGoogle Scholar
  64. 64.
    Laurin N, Brown JP, Lemainque A, Duchesne A, Huot D, Lacourciere Y, Drapeau G, Verreault J, Raymond V, Morissette J (2001) Paget disease of bone: mapping of two loci at 5q35-qter and 5q31. Am J Hum Genet 69:528–543PubMedCrossRefGoogle Scholar
  65. 65.
    Laurin N, Brown JP, Morissette J, Raymond V (2002) Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet 70:1582–1588PubMedCrossRefGoogle Scholar
  66. 66.
    Hocking LJ, Lucas GJA, Daroszewska A, Mangion J, Olavesen M, Nicholson GC, Ward L, Bennett ST, Wuyts W, Van Hul W, Ralston SH (2002) Domain specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget’s disease. Hum Mol Genet 11:2735–2739PubMedCrossRefGoogle Scholar
  67. 67.
    Bolland MJ, Tong PC, Naot D, Callon KE, Wattie DJ, Gamble GD, Cundy T (2007) Delayed development of Paget’s disease in offspring inheriting SQSTM1 mutations. J Bone Miner Res 22:411–415PubMedCrossRefGoogle Scholar
  68. 68.
    Cavey JR, Ralston SH, Sheppard PW, Ciani B, Gallagher TR, Long JE, Searle MS, Layfield R (2006) Loss of ubiquitin binding is a unifying mechanism by which mutations of SQSTM1 cause Paget’s disease of bone. Calcif Tissue Int 78:271–277PubMedCrossRefGoogle Scholar
  69. 69.
    Layfield R, Hocking LJ (2004) SQSTM1 and Paget’s disease of bone. Calcif Tissue Int 75:347–357PubMedCrossRefGoogle Scholar
  70. 70.
    Tan JM, Wong ES, Dawson VL, Dawson TM, Lim KL (2007) Lysine 63-linked polyubiquitin potentially partners with p62 to promote the clearance of protein inclusions by autophagy. Autophagy 4:251–253Google Scholar
  71. 71.
    Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Overvatn A, Bjorkoy G, Johansen T (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282:24131–24145PubMedCrossRefGoogle Scholar
  72. 72.
    Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H, Johansen T (2005) p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171:603–614PubMedCrossRefGoogle Scholar
  73. 73.
    Visconti MR, Langston AL, Alonso N, Goodman K, Selby PL, Fraser WD, Ralston SH (2010) Mutations of SQSTM1 are associated with severity and clinical outcome in Paget’s disease of bone. J Bone Miner Res 25:2368–2373PubMedCrossRefGoogle Scholar
  74. 74.
    Beyens G, Van Hul E, Van Driessche K, Fransen E, Devogelaer J-P, Vanhoenacker F, Van Offel J, Verbruggen L, De Clerck L, Westhovens R, Van Hul W (2004) Evaluation of the role of the SQSTM1 gene in sporadic Belgian patients with Paget’s disease. Calcif Tissue Int 75:144–152PubMedCrossRefGoogle Scholar
  75. 75.
    Tanaka S, Takahashi N, Udagawa N, Tamura T, Akatsu T, Stanley ER, Kurokawa T, Suda T (1993) Macrophage colony-stimulating factor is indispensable for both proliferation and differentiation of osteoclast progenitors. J Clin Invest 91:257–263PubMedCrossRefGoogle Scholar
  76. 76.
    Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD, Nishikawa S (1990) The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345:442–444PubMedCrossRefGoogle Scholar
  77. 77.
    Van Wesenbeeck L, Odgren PR, MacKay CA, D’Angelo M, Safadi FF, Popoff SN, Van Hul W, Marks SC Jr (2002) The osteopetrotic mutation toothless (tl) is a loss-of-function frameshift mutation in the rat Csf1 gene: evidence of a crucial role for CSF-1 in osteoclastogenesis and endochondral ossification. Proc Natl Acad Sci USA 99:14303–14308PubMedCrossRefGoogle Scholar
  78. 78.
    Morohashi T, Corboz VA, Fleisch H, Cecchini MG, Felix R (1994) Macrophage colony-stimulating factor restores bone resorption in op/op bone in vitro in conjunction with parathyroid hormone or 1,25-dihydroxyvitamin D3. J Bone Miner Res 9:401–407PubMedCrossRefGoogle Scholar
  79. 79.
    Li J, Sarosi I, Yan XQ, Morony S, Capparelli C, Tan HL, McCabe S, Elliott R, Scully S, Van G, Kaufman S, Juan SC, Sun Y, Tarpley J, Martin L, Christensen K, McCabe J, Kostenuik P, Hsu H, Fletcher F, Dunstan CR, Lacey DL, Boyle WJ (2000) RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA 97:1566–1571PubMedCrossRefGoogle Scholar
  80. 80.
    Wallace RG, Barr RJ, Osterberg PH, Mollan RA (1989) Familial expansile osteolysis. Clin Orthop 248:265–277PubMedGoogle Scholar
  81. 81.
    Hughes AE, Shearman AM, Weber JL, Barr RJ, Wallace RG, Osterberg PH, Nevin NC, Mollan RA (1994) Genetic linkage of familial expansile osteolysis to chromosome 18q. Hum Mol Genet 3:359–361PubMedCrossRefGoogle Scholar
  82. 82.
    Haslam SI, Van Hul W, Morales-Piga A, Balemans W, San Millan JL, Nakatsuka K, Willems P, Haites NE, Ralston SH (1998) Paget’s disease of bone: evidence for a susceptibility locus on chromosome 18q and for genetic heterogeneity. J Bone Miner Res 13:911–917PubMedCrossRefGoogle Scholar
  83. 83.
    Hughes AE, Ralston SH, Marken J, Bell C, MacPherson H, Wallace RG, Van Hul W, Whyte MP, Nakatsuka K, Hovy L, Anderson DM (2000) Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet 24:45–48PubMedCrossRefGoogle Scholar
  84. 84.
    Nakatsuka K, Nishizawa Y, Ralston SH (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 18:1381–1385PubMedCrossRefGoogle Scholar
  85. 85.
    Whyte MP, 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 17:26–29PubMedCrossRefGoogle Scholar
  86. 86.
    Whyte MP, Mills BG, Reinus WR, Podgornik MN, Roodman GD, Gannon FH, Eddy MC, McAlister WH (2000) Expansile skeletal hyperphosphatasia: a new familial metabolic bone disease. J Bone Miner Res 15:2330–2344PubMedCrossRefGoogle Scholar
  87. 87.
    Crockett JC, Mellis DJ, Shennan KI, Duthie A, Greenhorn J, Scott DI, Ralston SH, Helfrich MH, Rogers MJ (2011) Signal peptide mutations in rank prevent downstream activation of NFkappaB. J Bone Miner Res 26:1926–1938PubMedCrossRefGoogle Scholar
  88. 88.
    Sparks AB, Peterson SN, Bell C, Loftus BJ, Hocking L, Cahill DP, Frassica FJ, Streeten EA, Levine MA, Fraser CM, Adams MD, Broder S, Venter JC, Kinzler KW, Vogelstein B, Ralston SH (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 68:151–155PubMedCrossRefGoogle Scholar
  89. 89.
    Wuyts W, Van Wesenbeeck L, Morales-Piga A, Ralston S, Hocking L, Vanhoenacker F, Westhovens R, Verbruggen L, Anderson D, Hughes A, Van Hul W (2001) Evaluation of the role of RANK and OPG genes in Paget’s disease of bone. Bone 28:104–107PubMedCrossRefGoogle Scholar
  90. 90.
    Chung PY, Beyens G, Riches PL, Van Wesenbeeck L, de Freitas F, Jennes K, Daroszewska A, Fransen E, Boonen S, Geusens P, Vanhoenacker F, Verbruggen L, Van Offel J, Goemaere S, Zmierczak HG, Westhovens R, Karperien M, Papapoulos S, Ralston SH, Devogelaer JP, Van Hul W (2010) Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget’s disease of bone. J Bone Miner Res 25:2316–2329CrossRefGoogle Scholar
  91. 91.
    Gianfrancesco F, Rendina D, Di Stefano M, Mingione A, Esposito T, Merlotti D, Gallone S, Magliocca S, Goode A, Formicola D, Morello G, Layfield R, Frattini A, De Filippo G, Nuti R, Searle M, Strazzullo P, Isaia G, Mossetti G, Gennari L (2011) A non-synonymous TNFRSF11A variation increases NFkB activity and the severity of Paget’s disease. J Bone Miner Res 27:443–452CrossRefGoogle Scholar
  92. 92.
    Zhu G, Wu CJ, Zhao Y, Ashwell JD (2007) Optineurin negatively regulates TNFalpha- induced NF-kappaB activation by competing with NEMO for ubiquitinated RIP. Curr Biol 17:1438–1443PubMedCrossRefGoogle Scholar
  93. 93.
    Wild P, Farhan H, McEwan DG, Wagner S, Rogov VV, Brady NR, Richter B, Korac J, Waidmann O, Choudhary C, Dotsch V, Bumann D, Dikic I (2011) Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333:228–233PubMedCrossRefGoogle Scholar
  94. 94.
    Rezaie T, Child A, Hitchings R, Brice G, Miller L, Coca-Prados M, Heon E, Krupin T, Ritch R, Kreutzer D, Crick RP, Sarfarazi M (2002) Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 295:1077–1079PubMedCrossRefGoogle Scholar
  95. 95.
    yala-Lugo RM, Pawar H, Reed DM, Lichter PR, Moroi SE, Page M, Eadie J, Azocar V, Maul E, Ntim-Amponsah C, Bromley W, Obeng-Nyarkoh E, Johnson AT, Kijek TG, Downs CA, Johnson JM, Perez-Grossmann RA, Guevara-Fujita ML, Fujita R, Wallace MR, Richards JE (2007) Variation in optineurin (OPTN) allele frequencies between and within populations. Mol Vis 13:151–163Google Scholar
  96. 96.
    Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H (2010) Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465:223–226PubMedCrossRefGoogle Scholar
  97. 97.
    Millecamps S, Boillee S, Chabrol E, Camu W, Cazeneuve C, Salachas F, Pradat PF, nel-Brunaud V, Vandenberghe N, Corcia P, Le Forestier N, Lacomblez L, Bruneteau G, Seilhean D, Brice A, Feingold J, Meininger V, Leguern E (2011) Screening of OPTN in French familial amyotrophic lateral sclerosis. Neurobiol Aging 32(3):557.e11–3Google Scholar
  98. 98.
    Nagabhushana A, Bansal M, Swarup G (2011) Optineurin is required for CYLD-dependent inhibition of TNFalpha-induced NF-kappaB activation. PLoS ONE 6:e17477PubMedCrossRefGoogle Scholar
  99. 99.
    Whyte MP, Obrecht SE, Finnegan PM, Jones JL, Podgornik MN, McAlister WH, Mumm S (2002) Osteoprotegerin deficiency and juvenile Paget’s disease. N Engl J Med 347:175–184PubMedCrossRefGoogle Scholar
  100. 100.
    Chong B, Hegde M, Fawkner M, Simonet S, Cassinelli H, Coker M, Kanis J, Seidel J, Tau C, Tuysuz B, Yuksel B, Love D, Cundy T (2003) Idiopathic hyperphosphatasia and TNFRSF11B mutations: relationships between phenotype and genotype. J Bone Miner Res 18:2095–2104PubMedCrossRefGoogle Scholar
  101. 101.
    Middleton-Hardie C, Zhu Q, Cundy H, Lin JM, Callon K, Tong PC, Xu J, Grey A, Cornish J, Naot D (2006) Deletion of aspartate 182 in OPG causes juvenile Paget’s disease by impairing both protein secretion and binding to RANKL. J Bone Miner Res 21:438–445PubMedCrossRefGoogle Scholar
  102. 102.
    Daroszewska A, Hocking LJ, McGuigan FEA, Langdahl BL, Stone MD, Cundy T, Nicholson GC, Fraser WD, Ralston SH (2004) Susceptibility to Paget’s disease of bone is influenced by a common polymorphic variant of osteoprotegerin. J Bone Miner Res 19:1506–1511PubMedCrossRefGoogle Scholar
  103. 103.
    Beyens G, Daroszewska A, de Freitas F, Fransen E, Vanhoenacker F, Verbruggen L, Zmierczak HG, Westhovens R, Van Offel J, Ralston SH, Devogelaer JP, Van Hul W (2007) Identification of sex-specific associations between polymorphisms of the osteoprotegerin gene, TNFRSF11B, and Paget’s disease of bone. J Bone Miner Res 22:1062–1071PubMedCrossRefGoogle Scholar
  104. 104.
    Grandi P, Dang T, Pane N, Shevchenko A, Mann M, Forbes D, Hurt E (1997) Nup93, a vertebrate homologue of yeast Nic96p, forms a complex with a novel 205 kDa protein and is required for correct nuclear pore assembly. Mol Biol Cell 8:2017–2038PubMedGoogle Scholar
  105. 105.
    Salomoni P, Pandolfi PP (2002) The role of PML in tumor suppression. Cell 108:165–170PubMedCrossRefGoogle Scholar
  106. 106.
    Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, Pestronk A, Whyte MP, Kimonis VE (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36:377–381PubMedCrossRefGoogle Scholar
  107. 107.
    Kimonis VE, Mehta SG, Fulchiero EC, Thomasova D, Pasquali M, Boycott K, Neilan EG, Kartashov A, Forman MS, Tucker S, Kimonis K, Mumm S, Whyte MP, Smith CD, Watts GD (2008) Clinical studies in familial VCP myopathy associated with Paget disease of bone and frontotemporal dementia. Am J Med Genet A 146:745–757Google Scholar
  108. 108.
    Kimonis VE, Kovach MJ, Waggoner B, Leal S, Salam A, Rimer L, Davis K, Khardori R, Gelber D (2000) Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone. Genet Med 2:232–241PubMedCrossRefGoogle Scholar
  109. 109.
    Meyer H, Bug M, Bremer S (2012) Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nat Cell Biol 14:117–123PubMedCrossRefGoogle Scholar
  110. 110.
    Richly H, Rape M, Braun S, Rumpf S, Hoege C, Jentsch S (2005) A series of ubiquitin binding factors connects CDC48/p97 to substrate multiubiquitylation and proteasomal targeting. Cell 120:73–84PubMedCrossRefGoogle Scholar
  111. 111.
    Hartmann-Petersen R, Wallace M, Hofmann K, Koch G, Johnsen AH, Hendil KB, Gordon C (2004) The Ubx2 and Ubx3 cofactors direct Cdc48 activity to proteolytic and nonproteolytic ubiquitin-dependent processes. Curr Biol 14:824–828PubMedCrossRefGoogle Scholar
  112. 112.
    Zhong X, Shen Y, Ballar P, Apostolou A, Agami R, Fang S (2004) AAA ATPase p97/valosin-containing protein interacts with gp78, a ubiquitin ligase for endoplasmic reticulum-associated degradation. J Biol Chem 279:45676–45684PubMedCrossRefGoogle Scholar
  113. 113.
    Tresse E, Salomons FA, Vesa J, Bott LC, Kimonis V, Yao TP, Dantuma NP, Taylor JP (2010) VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD. Autophagy 6:217–227PubMedCrossRefGoogle Scholar
  114. 114.
    Weihl CC, Miller SE, Hanson PI, Pestronk A (2007) Transgenic expression of inclusion body myopathy associated mutant p97/VCP causes weakness and ubiquitinated protein inclusions in mice. Hum Mol Genet 16:919–928PubMedCrossRefGoogle Scholar
  115. 115.
    Muller JM, Deinhardt K, Rosewell I, Warren G, Shima DT (2007) Targeted deletion of p97 (VCP/CDC48) in mouse results in early embryonic lethality. Biochem Biophys Res Commun 354:459–465PubMedCrossRefGoogle Scholar
  116. 116.
    Weihl CC, Dalal S, Pestronk A, Hanson PI (2006) Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation. Hum Mol Genet 15:189–199PubMedCrossRefGoogle Scholar
  117. 117.
    Badadani M, Nalbandian A, Watts GD, Vesa J, Kitazawa M, Su H, Tanaja J, Dec E, Wallace DC, Mukherjee J, Caiozzo V, Warman M, Kimonis VE (2010) VCP associated inclusion body myopathy and Paget disease of bone knock-in mouse model exhibits tissue pathology typical of human disease. PLoS ONE 5:e13183PubMedCrossRefGoogle Scholar
  118. 118.
    Ritz D, Vuk M, Kirchner P, Bug M, Schutz S, Hayer A, Bremer S, Lusk C, Baloh RH, Lee H, Glatter T, Gstaiger M, Aebersold R, Weihl CC, Meyer H (2011) Endolysosomal sorting of ubiquitylated caveolin-1 is regulated by VCP and UBXD1 and impaired by VCP disease mutations. Nat Cell Biol 13:1116–1123PubMedCrossRefGoogle Scholar
  119. 119.
    Lucas GJ, Mehta SG, Hocking LJ, Stewart TL, Cundy T, Nicholson GC, Walsh JP, Fraser WD, Watts GD, Ralston SH, Kimonis VE (2006) Evaluation of the role of Valosin-containing protein in the pathogenesis of familial and sporadic Paget’s disease of bone. Bone 38:280–285PubMedCrossRefGoogle Scholar
  120. 120.
    Chung PY, Beyens G, de Freitas F, Boonen S, Geusens P, Vanhoenacker F, Verbruggen L, Van Offel J, Goemaere S, Zmierczak HG, Westhovens R, Devogelaer JP, Van Hul W (2011) Indications for a genetic association of a VCP polymorphism with the pathogenesis of sporadic Paget’s disease of bone, but not for TNFSF11 (RANKL) and IL-6 polymorphisms. Mol Genet Metab 103:287–292PubMedCrossRefGoogle Scholar
  121. 121.
    Ralston SH (1993) Paget’s disease of bone. Br Med J 306:332–333CrossRefGoogle Scholar
  122. 122.
    Merchant A, Smielewska M, Patel N, Akunowicz JD, Saria EA, Delaney JD, Leach RJ, Seton M, Hansen MF (2009) Somatic mutations in SQSTM1 detected in affected tissues from patients with sporadic Paget’s disease of bone. J Bone Miner Res 24:484–494PubMedCrossRefGoogle Scholar
  123. 123.
    Matthews BG, Naot D, Bava U, Callon KE, Pitto RP, McCowan SA, Wattie D, Cundy T, Cornish J, Reid IR (2009) Absence of somatic SQSTM1 mutations in Paget’s disease of bone. J Clin Endocrinol Metab 94:691–694PubMedCrossRefGoogle Scholar
  124. 124.
    Goode A, Layfield R (2010) Recent advances in understanding the molecular basis of Paget disease of bone. J Clin Pathol 63:199–203PubMedCrossRefGoogle Scholar
  125. 125.
    Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, Jimenez-Sanchez M, Korolchuk VI, Lichtenberg M, Luo S, Massey DC, Menzies FM, Moreau K, Narayanan U, Renna M, Siddiqi FH, Underwood BR, Winslow AR, Rubinsztein DC (2010) Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 90:1383–1435PubMedCrossRefGoogle Scholar
  126. 126.
    Kim PK, Hailey DW, Mullen RT, Lippincott-Schwartz J (2008) Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes. Proc Natl Acad Sci USA 105:20567–20574PubMedCrossRefGoogle Scholar
  127. 127.
    Whitehouse CA, Waters S, Marchbank K, Horner A, McGowan NW, Jovanovic JV, Xavier GM, Kashima TG, Cobourne MT, Richards GO, Sharpe PT, Skerry TM, Grigoriadis AE, Solomon E (2010) Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity. Proc Natl Acad Sci USA 107:12913–12918PubMedCrossRefGoogle Scholar
  128. 128.
    Kirkin V, Lamark T, Johansen T, Dikic I (2009) NBR1 cooperates with p62 in selective autophagy of ubiquitinated targets. Autophagy 5:732–733PubMedCrossRefGoogle Scholar
  129. 129.
    Collet C, Michou L, Audran M, Chasseigneaux S, Hilliquin P, Bardin T, Lemaire I, Cornelis F, Launay JM, Orcel P, Laplanche JL (2007) Paget’s disease of bone in the French population: novel SQSTM1 mutations, functional analysis, and genotype–phenotype correlations. J Bone Miner Res 22:310–317PubMedCrossRefGoogle Scholar
  130. 130.
    Ju JS, Fuentealba RA, Miller SE, Jackson E, Piwnica-Worms D, Baloh RH, Weihl CC (2009) Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J Cell Biol 187:875–888PubMedCrossRefGoogle Scholar
  131. 131.
    DeSelm CJ, Miller BC, Zou W, Beatty WL, van Meel E, Takahata Y, Klumperman J, Tooze SA, Teitelbaum SL, Virgin HW (2011) Autophagy proteins regulate the secretory component of osteoclastic bone resorption. Dev Cell 21:966–974PubMedCrossRefGoogle Scholar
  132. 132.
    Mills BG, Singer FR (1976) Nuclear inclusions in Paget’s disease of bone. Science 194:201–202PubMedCrossRefGoogle Scholar
  133. 133.
    Mills BG, Frausto A, Singer FR, Ohsaki Y, Demulder A, Roodman GD (1994) Multinucleated cells formed in vitro from Paget’s bone marrow express viral antigens. Bone 15:443–448PubMedCrossRefGoogle Scholar
  134. 134.
    Rebel A, Basle M, Pouplard A, Malkani K, Filmon R, Lepatezour A (1980) Bone tissue in Paget’s disease of bone. Ultrastructure and immunocytology. Arthritis Rheum 23:1104–1114PubMedCrossRefGoogle Scholar
  135. 135.
    Mills BG, Singer FR, Weiner LP, Holst PA (1981) Immunohistological demonstration of respiratory syncytial virus antigens in Paget’s disease of bone. Proc Natl Acad Sci USA 78:1209–1212PubMedCrossRefGoogle Scholar
  136. 136.
    Khan SA, Brennan P, Newman J, Gray RE, McCloskey EV, Kanis JA (1996) Paget’s disease of bone and unvaccinated dogs. Bone 19:47–50PubMedCrossRefGoogle Scholar
  137. 137.
    Siris ES, Kelsey JL, Flaster E, Parker S (1990) Paget’s disease of bone and previous pet ownership in the United States: dogs exonerated. Int J Epidemiol 19:455–458PubMedCrossRefGoogle Scholar
  138. 138.
    Gordon MT, Anderson DC, Sharpe PT (1991) Canine distemper virus localised in bone cells of patients with Paget’s disease. Bone 12:195–201PubMedCrossRefGoogle Scholar
  139. 139.
    Mee AP, Dixon JA, Hoyland JA, Davies M, Selby PL, Mawer EB (1998) Detection of canine distemper virus in 100 % of Paget’s disease samples by in situ-reverse transcriptase polymerase chain reaction. Bone 23:171–175PubMedCrossRefGoogle Scholar
  140. 140.
    Gordon MT, Mee AP, Anderson DC, Sharpe PT (1992) Canine distemper transcripts sequenced from pagetic bone. Bone Miner 19:159–174PubMedCrossRefGoogle Scholar
  141. 141.
    Basle MF, Fournier JG, Rozenblatt S, Rebel A, Bouteille M (1986) Measles virus RNA detected in Paget’s disease bone tissue by in situ hybridization. J Gen Virol 67(Pt 5):907–913PubMedCrossRefGoogle Scholar
  142. 142.
    Reddy SV, Menaa C, Singer FR, Cundy T, Cornish J, Whyte MP, Roodman GD (1999) Measles virus nucleocapsid transcript expression is not restricted to the osteoclast lineage in patients with Paget’s disease of bone. Exp Hematol 27:1528–1532PubMedCrossRefGoogle Scholar
  143. 143.
    Ralston SH, DiGiovine FS, Gallacher SJ, Boyle IT, Duff GW (1991) Failure to detect paramyxovirus sequences in Paget’s disease of bone using the polymerase chain reaction. J Bone Miner Res 6:1243–1248PubMedCrossRefGoogle Scholar
  144. 144.
    Birch MA, Taylor W, Fraser WD, Ralston SH, Hart CA, Gallagher JA (1994) Absence of paramyxovirus RNA in cultures of pagetic bone cells and in pagetic bone. J Bone Miner Res 9:11–16PubMedCrossRefGoogle Scholar
  145. 145.
    Ooi CG, Walsh CA, Gallagher JA, Fraser WD (2000) Absence of measles virus and canine distemper virus transcripts in long-term bone marrow cultures from patients with Paget’s disease of bone. Bone 27:417–421PubMedCrossRefGoogle Scholar
  146. 146.
    Nuovo MA, Nuovo GJ, MacConnell P, Forde A, Steiner GC (1992) In situ analysis of Paget’s disease of bone for measles-specific PCR-amplified cDNA. Diagn Mol Pathol 1:256–265PubMedGoogle Scholar
  147. 147.
    Friedrichs WE, Reddy SV, Bruder JM, Cundy T, Cornish J, Singer FR, Roodman GD (2002) Sequence analysis of measles virus nucleocapsid transcripts in patients with Paget’s disease. J Bone Miner Res 17:145–151PubMedCrossRefGoogle Scholar
  148. 148.
    Matthews BG, Afzal MA, Minor PD, Bava U, Callon KE, Pitto RP, Cundy T, Cornish J, Reid IR, Naot D (2008) Failure to detect measles virus RNA in bone cells from patients with Paget’s disease. J Clin Endocrinol Metab 93:1398–1401PubMedCrossRefGoogle Scholar
  149. 149.
    Mee AP, May C, Bennett D, Sharpe PT (1995) Generation of multinucleated osteoclast-like cells from canine bone marrow: effects of canine distemper virus. Bone 17:47–55PubMedCrossRefGoogle Scholar
  150. 150.
    Reddy SV, Kurihara N, Menaa C, Landucci G, Forthal D, Koop BA, Windle JJ, Roodman GD (2001) Osteoclasts formed by measles virus-infected osteoclast precursors from hCD46 transgenic mice express characteristics of pagetic osteoclasts. Endocrinology 142:2898–2905PubMedCrossRefGoogle Scholar
  151. 151.
    Kurihara N, Reddy SV, Menaa C, Anderson D, Roodman GD (2000) Osteoclasts expressing the measles virus nucleocapsid gene display a pagetic phenotype. J Clin Invest 105:607–614PubMedCrossRefGoogle Scholar
  152. 152.
    Kurihara N, Hiruma Y, Yamana K, Michou L, Rousseau C, Morissette J, Galson DL, Teramachi J, Zhou H, Dempster DW, Windle JJ, Brown JP, Roodman GD (2011) Contributions of the measles virus nucleocapsid gene and the SQSTM1/p62(P392L) mutation to Paget’s disease. Cell Metab 13:23–34PubMedCrossRefGoogle Scholar
  153. 153.
    Kurihara N, Zhou H, Reddy SV, Garcia Palacios V, Subler MA, Dempster DW, Windle JJ, Roodman GD (2006) Expression of measles virus nucleocapsid protein in osteoclasts induces Paget’s disease-like bone lesions in mice. J Bone Miner Res 21:446–455PubMedCrossRefGoogle Scholar
  154. 154.
    Ruddle NH, Li CB, Horne WC, Santiago P, Troiano N, Jay G, Horowitz Baron R (1993) Mice transgenic for HTLV-I LTR-tax exhibit tax expression in bone, skeletal alterations, and high bone turnover. Virology 197:196–204PubMedCrossRefGoogle Scholar
  155. 155.
    Hiruma Y, Kurihara N, Subler MA, Zhou H, Boykin CS, Zhang H, Ishizuka S, Dempster DW, Roodman GD, Windle JJ (2008) A SQSTM1/p62 mutation linked to Paget’s disease increases the osteoclastogenic potential of the bone microenvironment. Hum Mol Genet 17:3708–3719PubMedCrossRefGoogle Scholar
  156. 156.
    Custer SK, Neumann M, Lu H, Wright AC, Taylor JP (2010) Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone. Hum Mol Genet 19:1741–1755PubMedCrossRefGoogle Scholar
  157. 157.
    Rea SL, Walsh JP, Ward L, Magno AL, Ward BK, Shaw B, Layfield R, Kent GN, Xu J, Ratajczak T (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-kappaB signaling without loss of ubiquitin-binding. J Bone Miner Res 24:1216–1223PubMedCrossRefGoogle Scholar
  158. 158.
    Johnson-Pais TL, Wisdom JH, Weldon KS, Cody JD, Hansen MF, Singer FR, Leach RJ (2003) Three novel mutations in SQSTM1 identified in familial Paget’s disease of bone. J Bone Miner Res 18:1748–1753PubMedCrossRefGoogle Scholar
  159. 159.
    Falchetti A, Di Stefano M, Marini F, Del Monte F, Mavilia C, Strigoli D, De Feo ML, Isaia G, Masi L, Amedei A, Cioppi F, Ghinoi V, Maddali Bongi S, Di Fede G, Sfrerrazza C, Rini GB, Melchiorre D, Matucci-Cerenic M, Brandi ML (2004) Two novel mutations at exon 8 of Sequestosome 1 gene (SQSTM1) in an Italian series of patients affected by Paget’s disease of bone (PDB). J Bone Miner Res 19:1013–1017PubMedCrossRefGoogle Scholar
  160. 160.
    Hocking LJ, Lucas GJA, Daroszewska A, Cundy T, Nicholson GC, Donath J, Walsh JP, Finlayson C, Cavey JR, Ciani B, Sheppard PW, Searle MS, Layfield R, Ralston SH (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 19:1122–1127PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Rheumatic Diseases Unit, Molecular Medicine Centre, Western General HospitalUniversity of EdinburghEdinburghUK
  2. 2.School of Biomedical SciencesUniversity of NottinghamNottinghamUK

Personalised recommendations