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Paget’s Disease of Bone: Osteoimmunology and Osteoclast Pathology

  • Autoimmunity (TK Tarrant, Section Editor)
  • Published:
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Abstract

Purpose of Review

The purpose of this review is to recognize clinical features of Paget’s disease of bone and to describe how the osteoclast, a myeloid-derived cell responsible for bone resorption, contributes to the disease.

Recent Findings

Recent studies have identified several variants in SQSTM1, OPTN, and other genes that may predispose individuals to Paget’s disease of bone; studies of these genes and their protein products have elucidated new roles for these proteins in bone physiology.

Summary

Understanding the pathologic mechanisms in the Pagetic osteoclast may lead to the identification of future treatment targets for other inflammatory and autoimmune diseases characterized by abnormal bone erosion and/or osteoclast activation.

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Abbreviations

ALP:

Alkaline phosphatase

BM:

Bone marrow

CTX:

C-terminal telopeptide of type I collagen

IFN:

Interferon

IL:

Interleukin

M-CSF:

Macrophage colony-stimulating factor

NFκB:

Nuclear Factor Kappa B

NFATc1:

Nuclear factor of activated T cells, cytoplasmic 1

NTX:

N-terminal telopeptide of type I collagen

PDB:

Paget’s disease of bone

OCL:

Osteoclast

OB:

Osteoblast

OPG:

Osteoprotegerin

P1NP:

Procollagen type I amino terminal peptide

RANK:

Receptor activator of NFκB

RANKL:

Receptor activator of NFκB ligand

SNP:

Single nucleotide polymorphisms

ZA:

Zoledronic acid

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Toodayan N. The Paget bicentenary: an Australian perspective. J Med Biogr. 2018;26(3):164–71.

    Article  PubMed  Google Scholar 

  2. Sabharwal R, Gupta S, Sepolia S, Panigrahi R, Mohanty S, Subudhi SK, et al. An insight in to Paget’s disease of bone. Niger J Surg. 2014;20(1):9–15.

    PubMed  PubMed Central  Google Scholar 

  3. Singer FR. Paget’s Disease of Bone. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, et al., editors. Endotext. South Dartmouth (MA) 2000.

  4. Daroszewska A, Rose L, Sarsam N, Charlesworth G, Prior A, Rose K, et al. Zoledronic acid prevents pagetic-like lesions and accelerated bone loss in the p62(P394L) mouse model of Paget’s disease. Dis Model Mech. 2018;11(9):dmm035576 Comment: primary research of a p62 mutation mouse model of Paget’s disease.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Gasper TM. Paget’s disease in a treadle machine operator. Br Med J. 1979;1(6172):1217–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Solomon LR. Billiard-player’s fingers: an unusual case of Paget’s disease of bone. Br Med J. 1979;1(6168):931.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mays S. Archaeological skeletons support a northwest European origin for Paget’s disease of bone. J Bone Miner Res. 2010;25(8):1839–41.

    Article  PubMed  Google Scholar 

  8. Kesterke MJ, Judd MA. A microscopic evaluation of Paget’s disease of bone from a Byzantine monastic crypt in Jordan. Int J Paleopathol. 2019;24:293–8.

    Article  PubMed  Google Scholar 

  9. Rogers J, Jeffrey DR, Watt I. Paget’s disease in an archeological population. J Bone Miner Res. 2002;17(6):1127–34.

    Article  CAS  PubMed  Google Scholar 

  10. Waldron HA. Recalculation of secular trends in Paget’s disease. J Bone Miner Res. 2004;19(3):523.

    Article  CAS  PubMed  Google Scholar 

  11. Pusch CM, Czarnetzki A. Archaeology and prevalence of Paget’s disease. J Bone Miner Res. 2005;20(8):1484 author reply 5.

    Article  PubMed  Google Scholar 

  12. Shaw B, Burrell CL, Green D, Navarro-Martinez A, Scott D, Daroszewska A, et al. Molecular insights into an ancient form of Paget’s disease of bone. Proc Natl Acad Sci U S A. 2019;116(21):10463–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wermers RA, Tiegs RD, Atkinson EJ, Achenbach SJ, Melton LJ 3rd. Morbidity and mortality associated with Paget’s disease of bone: a population-based study. J Bone Miner Res. 2008;23(6):819–25.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Shaker JL. Paget’s disease of bone: a review of epidemiology, pathophysiology and management. Ther Adv Musculoskelet Dis. 2009;1(2):107–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tan A, Ralston SH. Clinical presentation of Paget’s disease: evaluation of a contemporary cohort and systematic review. Calcif Tissue Int. 2014;95(5):385–92.

    Article  CAS  PubMed  Google Scholar 

  16. Winfield J, Stamp TC. Bone and joint symptoms in Paget’s disease. Ann Rheum Dis. 1984;43(6):769–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Alvarez L, Guanabens N, Peris P, Monegal A, Bedini JL, Deulofeu R, et al. Discriminative value of biochemical markers of bone turnover in assessing the activity of Paget’s disease. J Bone Miner Res. 1995;10(3):458–65.

    Article  CAS  PubMed  Google Scholar 

  18. Gennari L, Rendina D, Falchetti A, Merlotti D. Paget’s disease of bone. Calcif Tissue Int. 2019;104(5):483–500.

    Article  CAS  PubMed  Google Scholar 

  19. Ralston SH, Corral-Gudino L, Cooper C, Francis RM, Fraser WD, Gennari L, et al. Diagnosis and management of paget’s disease of bone in adults: a clinical guideline. J Bone Miner Res. 2019;34(4):579–604.

    Article  PubMed  Google Scholar 

  20. Seton M. Paget disease of bone: diagnosis and drug therapy. Cleve Clin J Med. 2013;80(7):452–62.

    Article  PubMed  Google Scholar 

  21. Seitz S, Priemel M, Zustin J, Beil FT, Semler J, Minne H, et al. Paget’s disease of bone: histologic analysis of 754 patients. J Bone Miner Res. 2009;24(1):62–9.

    Article  PubMed  Google Scholar 

  22. Rebel A, Malkani K, Basle M, Bregeon C. Is Paget’s disease of bone a viral infection? Calcif Tissue Res. 1977;22(Suppl):283–6.

    PubMed  Google Scholar 

  23. Mills BG, Singer FR. Nuclear inclusions in Paget’s disease of bone. Science. 1976;194(4261):201–2.

    Article  CAS  PubMed  Google Scholar 

  24. Nebot Valenzuela E, Pietschmann P. Epidemiology and pathology of Paget’s disease of bone - a review. Wien Med Wochenschr. 2017;167(1-2):2–8.

    Article  PubMed  Google Scholar 

  25. Reid IR. Recent advances in understanding and managing Paget’s disease. F1000Res. 2019;8.

  26. Stanislavsky A Polyostotic Paget Disease 2011 [Available from: https://radiopaedia.org/cases/polyostotic-paget-disease?lang=us.

  27. Singer FR. Paget’s disease of bone-genetic and environmental factors. Nat Rev Endocrinol. 2015;11(11):662–71.

    Article  CAS  PubMed  Google Scholar 

  28. Singer FR, Bone HG 3rd, Hosking DJ, Lyles KW, Murad MH, Reid IR, et al. Paget’s disease of bone: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(12):4408–22.

    Article  CAS  PubMed  Google Scholar 

  29. Winn N, Lalam R, Cassar-Pullicino V. Imaging of Paget’s disease of bone. Wien Med Wochenschr. 2017;167(1-2):9–17.

    Article  PubMed  Google Scholar 

  30. Monsell EM. The mechanism of hearing loss in Paget’s disease of bone. Laryngoscope. 2004;114(4):598–606.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lyles KW, Gold DT, Newton RA, Parekh S, Shipp KM, Pieper CF, et al. Peyronie’s disease is associated with Paget’s disease of bone. J Bone Miner Res. 1997;12(6):929–34.

    Article  CAS  PubMed  Google Scholar 

  32. Reid IR, Miller P, Lyles K, Fraser W, Brown JP, Saidi Y, et al. Comparison of a single infusion of zoledronic acid with risedronate for Paget’s disease. N Engl J Med. 2005;353(9):898–908.

    Article  CAS  PubMed  Google Scholar 

  33. Seton M, Krane SM. Use of zoledronic acid in the treatment of Paget’s disease. Ther Clin Risk Manag. 2007;3(5):913–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Hosking D, Lyles K, Brown JP, Fraser WD, Miller P, Curiel MD, et al. Long-term control of bone turnover in Paget’s disease with zoledronic acid and risedronate. J Bone Miner Res. 2007;22(1):142–8.

    Article  CAS  PubMed  Google Scholar 

  35. Siris E, Weinstein RS, Altman R, Conte JM, Favus M, Lombardi A, et al. Comparative study of alendronate versus etidronate for the treatment of Paget’s disease of bone. J Clin Endocrinol Metab. 1996;81(3):961–7.

    CAS  PubMed  Google Scholar 

  36. Walsh JP, Ward LC, Stewart GO, Will RK, Criddle RA, Prince RL, et al. A randomized clinical trial comparing oral alendronate and intravenous pamidronate for the treatment of Paget’s disease of bone. Bone. 2004;34(4):747–54.

    Article  CAS  PubMed  Google Scholar 

  37. Miller PD, Brown JP, Siris ES, Hoseyni MS, Axelrod DW, Bekker PJ. A randomized, double-blind comparison of risedronate and etidronate in the treatment of Paget’s disease of bone. Paget’s Risedronate/Etidronate Study Group. Am J Med. 1999;106(5):513–20.

    Article  CAS  PubMed  Google Scholar 

  38. Rendina D, Mossetti G, Viceconti R, Sorrentino M, Nunziata V. Risedronate and pamidronate treatment in the clinical management of patients with severe Paget’s disease of bone and acquired resistance to bisphosphonates. Calcif Tissue Int. 2004;75(3):189–96.

    Article  CAS  PubMed  Google Scholar 

  39. Wat WZ. Current perspectives on bisphosphonate treatment in Paget’s disease of bone. Ther Clin Risk Manag. 2014;10:977–83.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Hocking LJ, Lucas GJ, Daroszewska A, Mangion J, Olavesen M, Cundy T, et al. Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget’s disease. Hum Mol Genet. 2002;11(22):2735–9.

    Article  CAS  PubMed  Google Scholar 

  41. Reid IR, Lyles K, Su G, Brown JP, Walsh JP, del Pino-Montes J, et al. A single infusion of zoledronic acid produces sustained remissions in Paget disease: data to 6.5 years. J Bone Miner Res. 2011;26(9):2261–70.

    Article  CAS  PubMed  Google Scholar 

  42. Cundy T, Maslowski K, Grey A, Reid IR. Durability of response to Zoledronate treatment and competing mortality in Paget’s disease of bone. J Bone Miner Res. 2017;32(4):753–6.

    Article  CAS  PubMed  Google Scholar 

  43. Langston AL, Campbell MK, Fraser WD, MacLennan GS, Selby PL, Ralston SH, et al. Randomized trial of intensive bisphosphonate treatment versus symptomatic management in Paget’s disease of bone. J Bone Miner Res. 2010;25(1):20–31.

    Article  CAS  PubMed  Google Scholar 

  44. Reid IR, Sharma S, Kalluru R, Eagleton C. Treatment of Paget’s disease of bone with denosumab: case report and literature review. Calcif Tissue Int. 2016;99(3):322–5.

    Article  CAS  PubMed  Google Scholar 

  45. Barry HC. Orthopedic aspects of Paget’s disease of bone. Arthritis Rheum. 1980;23(10):1128–30.

    Article  CAS  PubMed  Google Scholar 

  46. Bidner S, Finnegan M. Femoral fractures in Paget’s disease. J Orthop Trauma. 1989;3(4):317–22.

    Article  CAS  PubMed  Google Scholar 

  47. Whitson HE, Lobaugh B, Lyles KW. Severe hypocalcemia following bisphosphonate treatment in a patient with Paget’s disease of bone. Bone. 2006;39(4):954–8.

    Article  CAS  PubMed  Google Scholar 

  48. Parvizi J, Klein GR, Sim FH. Surgical management of Paget’s disease of bone. J Bone Miner Res. 2006;21(Suppl 2):P75–82.

    Article  PubMed  Google Scholar 

  49. Calderoni P, Ferruzzi A, Andreoli I, Gualtieri G. Hip arthroplasty in coxarthrosis secondary to Paget’s disease. Chir Organi Mov. 2002;87(1):43–8.

    CAS  PubMed  Google Scholar 

  50. Wootton R, Reeve J, Spellacy E, Tellez-Yudilevich M. Skeletal blood flow in Paget’s disease of bone and its response to calcitonin therapy. Clin Sci Mol Med. 1978;54(1):69–74.

    CAS  PubMed  Google Scholar 

  51. Roodman GD. Insights into the pathogenesis of Paget’s disease. Ann N Y Acad Sci. 2010;1192:176–80.

    Article  CAS  PubMed  Google Scholar 

  52. Numan MS, Jean S, Dessay M, Gagnon E, Amiable N, Brown JP, et al. Gene-environment interactions in Paget’s disease of bone. Joint Bone Spine. 2019;86(3):373–80.

    Article  CAS  PubMed  Google Scholar 

  53. Haddaway MJ, Davie MW, McCall IW, Howdle S. Effect of age and gender on the number and distribution of sites in Paget’s disease of bone. Br J Radiol. 2007;80(955):532–6.

    Article  CAS  PubMed  Google Scholar 

  54. Beyens G, Daroszewska A, de Freitas F, Fransen E, Vanhoenacker F, Verbruggen L, 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(7):1062–71.

    Article  CAS  PubMed  Google Scholar 

  55. Wong SW, Huang BW, Hu X, Ho Kim E, Kolb JP, Padilla RJ, et al. Global deletion of Optineurin results in altered type I IFN signaling and abnormal bone remodeling in a model of Paget’s disease. Cell Death Differ. 2020;27(1):71–84 Comment: primary research of an optineurin-deficient mouse model of Paget’s disease.

    Article  CAS  PubMed  Google Scholar 

  56. Morales-Piga AA, Rey-Rey JS, Corres-Gonzalez J, Garcia-Sagredo JM, Lopez-Abente G. Frequency and characteristics of familial aggregation of Paget’s disease of bone. J Bone Miner Res. 1995;10(4):663–70.

    Article  CAS  PubMed  Google Scholar 

  57. Seton M, Choi HK, Hansen MF, Sebaldt RJ, Cooper C. Analysis of environmental factors in familial versus sporadic Paget’s disease of bone--the New England Registry for Paget’s Disease of Bone. J Bone Miner Res. 2003;18(8):1519–24.

    Article  PubMed  Google Scholar 

  58. Merashli M, Jawad A. Paget’s Disease of Bone among Various Ethnic Groups. Sultan Qaboos Univ Med J. 2015;15(1):e22–6.

    PubMed  PubMed Central  Google Scholar 

  59. Cundy T. Paget’s disease of bone. Metabolism. 2018;80:5–14 Comment: recent comprehensive review of Paget’s Disease of Bone.

    Article  CAS  PubMed  Google Scholar 

  60. Merlotti D, Gennari L, Galli B, Martini G, Calabro A, De Paola V, et al. Characteristics and familial aggregation of Paget’s disease of bone in Italy. J Bone Miner Res. 2005;20(8):1356–64.

    Article  PubMed  Google Scholar 

  61. Audet MC, Jean S, Beaudoin C, Guay-Belanger S, Dumont J, Brown JP, et al. Environmental factors associated with familial or non-familial forms of Paget’s disease of bone. Joint Bone Spine. 2017;84(6):719–23.

    Article  PubMed  Google Scholar 

  62. Michou L, Collet C, Morissette J, Audran M, Thomas T, Gagnon E, et al. Epidemiogenetic study of French families with Paget’s disease of bone. Joint Bone Spine. 2012;79(4):393–8.

    Article  PubMed  Google Scholar 

  63. Siris ES. Epidemiological aspects of Paget’s disease: family history and relationship to other medical conditions. Semin Arthritis Rheum. 1994;23(4):222–5.

    Article  CAS  PubMed  Google Scholar 

  64. Barker DJ, Gardner MJ. Distribution of Paget’s disease in England, Wales and Scotland and a possible relationship with vitamin D deficiency in childhood. Br J Prev Soc Med. 1974;28(4):226–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Lever JH. Paget’s disease of bone in Lancashire and arsenic pesticide in cotton mill wastewater: a speculative hypothesis. Bone. 2002;31(3):434–6.

    Article  CAS  PubMed  Google Scholar 

  66. 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(3):247–51.

    Article  CAS  PubMed  Google Scholar 

  67. Ralston SH, Layfield R. Pathogenesis of Paget disease of bone. Calcif Tissue Int. 2012;91(2):97–113.

    Article  CAS  PubMed  Google Scholar 

  68. Singer FR. Update on the viral etiology of Paget’s disease of bone. J Bone Miner Res. 1999;14(Suppl 2):29–33.

    Article  PubMed  Google Scholar 

  69. Ehrlich LA, Roodman GD. The role of immune cells and inflammatory cytokines in Paget’s disease and multiple myeloma. Immunol Rev. 2005;208:252–66.

    Article  CAS  PubMed  Google Scholar 

  70. Matthews BG, Afzal MA, Minor PD, Bava U, Callon KE, Pitto RP, et al. Failure to detect measles virus ribonucleic acid in bone cells from patients with Paget’s disease. J Clin Endocrinol Metab. 2008;93(4):1398–401.

    Article  CAS  PubMed  Google Scholar 

  71. Visconti MR, Usategui-Martin R, Ralston SH. Antibody response to Paramyxoviruses in Paget’s disease of bone. Calcif Tissue Int. 2017;101(2):141–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ralston SH, Afzal MA, Helfrich MH, Fraser WD, Gallagher JA, Mee A, 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(4):569–77.

    Article  CAS  PubMed  Google Scholar 

  73. Helfrich MH, Hobson RP, Grabowski PS, Zurbriggen A, Cosby SL, Dickson GR, et al. 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. 2000;15(12):2315–29.

    Article  CAS  PubMed  Google Scholar 

  74. Birch MA, Taylor W, Fraser WD, Ralston SH, Hart CA, Gallagher JA. Absence of paramyxovirus RNA in cultures of pagetic bone cells and in pagetic bone. J Bone Miner Res. 1994;9(1):11–6.

    Article  CAS  PubMed  Google Scholar 

  75. Roodman GD, Windle JJ. Paget disease of bone. J Clin Invest. 2005;115(2):200–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Tsukasaki M, Takayanagi H. Osteoimmunology: evolving concepts in bone-immune interactions in health and disease. Nat Rev Immunol. 2019;19(10):626–42 Comment: recent review of osteoimmunology.

    Article  CAS  PubMed  Google Scholar 

  77. Li Y, Toraldo G, Li A, Yang X, Zhang H, Qian WP, et al. B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo. Blood. 2007;109(9):3839–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Raggatt LJ, Partridge NC. Cellular and molecular mechanisms of bone remodeling. J Biol Chem. 2010;285(33):25103–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Amarasekara DS, Yun H, Kim S, Lee N, Kim H, Rho J. Regulation of osteoclast differentiation by cytokine networks. Immune Netw. 2018;18(1):e8.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Kollet O, Dar A, Shivtiel S, Kalinkovich A, Lapid K, Sztainberg Y, et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med. 2006;12(6):657–64.

    Article  CAS  PubMed  Google Scholar 

  81. Okamoto K, Nakashima T, Shinohara M, Negishi-Koga T, Komatsu N, Terashima A, et al. Osteoimmunology: the conceptual framework unifying the immune and skeletal systems. Physiol Rev. 2017;97(4):1295–349 Comment: recent reivew of osteoimmunology.

    Article  CAS  PubMed  Google Scholar 

  82. Mercier FE, Ragu C, Scadden DT. The bone marrow at the crossroads of blood and immunity. Nat Rev Immunol. 2011;12(1):49–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Brozowski JM, Billard MJ, Tarrant TK. Targeting the molecular and cellular interactions of the bone marrow niche in immunologic disease. Curr Allergy Asthma Rep. 2014;14(2):402 Comment: review of the bone marrow niche components.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Madel MB, Ibanez L, Wakkach A, de Vries TJ, Teti A, Apparailly F, et al. Immune Function and Diversity of Osteoclasts in Normal and Pathological Conditions. Front Immunol. 2019;10:1408 Comment: recent review on osteoclast physiology and roles in immunology.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ralston SH, Taylor JP. Rare Inherited forms of Paget’s Disease and Related Syndromes. Calcif Tissue Int. 2019;104(5):501–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Daroszewska A, van’t Hof RJ, Rojas JA, Layfield R, Landao-Basonga E, Rose L, 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(14):2734–44.

    Article  CAS  PubMed  Google Scholar 

  87. 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(6):1582–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Albagha OM, Visconti MR, Alonso N, Langston AL, Cundy T, Dargie R, 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(6):520–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Obaid R, Wani SE, Azfer A, Hurd T, Jones R, Cohen P, et al. Optineurin negatively regulates osteoclast differentiation by modulating NF-kappaB and interferon signaling: implications for Paget’s disease. Cell Rep. 2015;13(6):1096–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Zhu G, Wu CJ, Zhao Y, Ashwell JD. Optineurin negatively regulates TNFalpha- induced NF-kappaB activation by competing with NEMO for ubiquitinated RIP. Curr Biol. 2007;17(16):1438–43.

    Article  CAS  PubMed  Google Scholar 

  91. Silva IAL, Conceicao N, Gagnon E, Caiado H, Brown JP, Gianfrancesco F, et al. Effect of genetic variants of OPTN in the pathophysiology of Paget’s disease of bone. Biochim Biophys Acta Mol basis Dis. 2018;1864(1):143–51.

    Article  CAS  PubMed  Google Scholar 

  92. Nakatsuka K, Nishizawa Y, Ralston SH. Phenotypic characterization of early onset Paget’s disease of bone caused by a 27-bp duplication in the TNFRSF11A gene. J Bone Miner Res. 2003;18(8):1381–5.

    Article  CAS  PubMed  Google Scholar 

  93. Iwamoto SJ, Rothman MS, Duan S, Baker JC, Mumm S, Whyte MP. Early-onset Paget’s disease of bone in a Mexican family caused by a novel tandem duplication (77dup27) in TNFRSF11A that encodes RANK. Bone. 2020;133:115224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Hughes AE, Ralston SH, Marken J, Bell C, MacPherson H, Wallace RG, et al. Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet. 2000;24(1):45–8.

    Article  CAS  PubMed  Google Scholar 

  95. Whyte MP, Obrecht SE, Finnegan PM, Jones JL, Podgornik MN, McAlister WH, et al. Osteoprotegerin deficiency and juvenile Paget’s disease. N Engl J Med. 2002;347(3):175–84.

    Article  CAS  PubMed  Google Scholar 

  96. Daroszewska A, Hocking LJ, McGuigan FE, Langdahl B, Stone MD, Cundy T, et al. Susceptibility to Paget’s disease of bone is influenced by a common polymorphic variant of osteoprotegerin. J Bone Miner Res. 2004;19(9):1506–11.

    Article  CAS  PubMed  Google Scholar 

  97. Daroszewska A, Ralston SH. Genetics of Paget’s disease of bone. Clin Sci (Lond). 2005;109(3):257–63.

    Article  CAS  Google Scholar 

  98. Albagha OM. Genetics of Paget’s disease of bone. Bonekey Rep. 2015;4:756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Galson DL, Roodman GD. Pathobiology of Paget’s Disease of Bone. J Bone Metab. 2014;21(2):85–98.

    Article  PubMed  PubMed Central  Google Scholar 

  100. 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(10):1668–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Roodman GD, Kurihara N, Ohsaki Y, Kukita A, Hosking D, Demulder A, et al. Interleukin 6. A potential autocrine/paracrine factor in Paget’s disease of bone. J Clin Invest. 1992;89(1):46–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Division of Rheumatology and Immunology, Department of Medicine, Duke University, DUMC #3874, 200 Trent Dr, Durham, NC, 27710, USA

    Emily M. Rabjohns, Rishi R. Rampersad & Teresa K. Tarrant

  2. Duke University, Durham, NC, USA

    Katlyn Hurst & Arin Ghosh

  3. Division of Rheumatology, Department of Medicine, Hospital del Salvador, Santiago, Chile

    Maria C. Cuellar

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  1. Emily M. Rabjohns
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  2. Katlyn Hurst
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  6. Teresa K. Tarrant
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Correspondence to Teresa K. Tarrant.

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Key Messages

1. Paget’s disease of bone is a metabolic bone disorder that occurs with advanced age; symptoms range from no symptoms to bone pain, pathologic fracture, bone deformity, and rarely may result in malignancy.

2. Paget’s disease of bone may be hereditary or sporadic; contributing factors likely include environmental exposures and specific genetic defects resulting in abnormal bone remodeling driven by changes in the osteoclast.

3. The primary cell type causing Paget’s disease of bone is the osteoclast, a cell of hematopoietic origin that resorbs bone matrix.

This article is part of the Topical Collection on Autoimmunity

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Rabjohns, E.M., Hurst, K., Ghosh, A. et al. Paget’s Disease of Bone: Osteoimmunology and Osteoclast Pathology. Curr Allergy Asthma Rep 21, 23 (2021). https://doi.org/10.1007/s11882-021-01001-2

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  • DOI: https://doi.org/10.1007/s11882-021-01001-2

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