J Bone Metab.  2014 May;21(2):85-98. 10.11005/jbm.2014.21.2.85.

Pathobiology of Paget's Disease of Bone

Affiliations
  • 1Department of Medicine/Hematology-Oncology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh PA, USA.
  • 2Department of Medicine/Hematology-Oncology, Indiana University, Indianapolis IN, USA. groodman@iu.edu
  • 3Veterans Administration Medical Center, Indianapolis, IN, USA.

Abstract

Paget's disease of bone is characterized by highly localized areas of increased bone resorption accompanied by exuberant, but aberrant new bone formation with the primary cellular abnormality in osteoclasts. Paget's disease provides an important paradigm for understanding the molecular mechanisms regulating both osteoclast formation and osteoclast-induced osteoblast activity. Both genetic and environmental etiologies have been implicated in Paget's disease, but their relative contributions are just beginning to be defined. To date, the only gene with mutations in the coding region linked to Paget's disease is sequestosome-1 (SQSTM1), which encodes the p62 protein, and these mutations lead to elevated cytokine activation of NF-B in osteoclasts but do not induce a "pagetic osteoclast" phenotype. Further, genetic mutations linked to Paget's appear insufficient to cause Paget's disease and additional susceptibility loci or environmental factors may be required. Among the environmental factors suggested to induce Paget's disease, chronic measles (MV) infection has been the most studied. Expression of the measles virus nucleocapsid gene (MVNP) in osteoclasts induces pagetic-like osteoclasts and bone lesions in mice. Further, mice expressing both MVNP in osteoclasts and germline mutant p62 develop dramatic pagetic bone lesions that were strikingly similar to those seen in patients with Paget's disease. Thus, interactions between environmental and genetic factors appear important to the development of Paget's disease. In this article we review the mechanisms responsible for the effects of mutant p62 gene expression and MVNP on osteoclast and osteoblast activity, and how they may contribute to the development of Paget's disease of bone.

Keyword

Osteoblasts; Osteoclasts; Paget's disease

MeSH Terms

Animals
Bone Resorption
Chronic Disease
Clinical Coding
Gene Expression
Humans
Measles
Measles virus
Mice
Nucleocapsid
Osteitis Deformans*
Osteoblasts
Osteoclasts
Osteogenesis
Phenotype

Figure

  • Fig. 1 Characteristics of the pagetic osteoclasts phenotype. OCL, osteoclasts; 1,25-(OH)2D3, 1,25-dihydroxy-vitamin D3; TAF12, TAF12 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 20kDa; RANKL, receptor activator of NF-kappaB ligand; TNF, tumor necrosis factor; IL-6, interleukin-6.

  • Fig. 2 Signaling pathways altered by MVNP and mutant p62. (A) MVNP increases active TBK1, which results in increased activation of NF-κB by direct phosphorylation of S536-p65 NF-κB, leading to activation and nuclear translocation. MVNP also decreases Sirt1 deacetylation of NF-κB, leading to increased NF-κB activity. Further TBK1 is required for MVNP to increase TAF12 and phosphoATF7, leading to hypersensitivity of VDR to 1,25(OH)2D3. (B) Binding of TNF-α and RANKL to their respective receptors activates RIP1 and TRAF6, respectively, by inducing K63-linked ubiquitination. The scaffold protein p62 has specific interactions domains for both RIP1 (ZZ domain) and TRAF6 (T6 domain), an N-terminal domain that binds aPKCs (PB1 domain) and a C-terminal UBA domain that associates with ubiquitin chains. Downstream signaling via p62 pathway activation aPKC leading to activation of NF-κB is negatively regulated by recruitment of the deubiquitinase Cyld by p62 UBA interaction with the polyubiquitin chains on Cyld, and consequent TNF-α and RANKL signal attenuation by Cyld deubiquitination of RIP1 and TRAF6, respectively. Since mutant p62 does not associate with and recruit Cyld to RIP1 and TRAF6, there is less cytokine signal attenuation and, therefore, increased NF-κB activation by these cytokines. MVNP, measles virus nucleocapsid protein; TBK1, TANK-binding kinase 1; NF-κB, nuclear factor-κB; TAF12, TAF12 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 20kDa; VDR, vitamin D receptor; 1,25(OH)2D3, 1,25-dihydroxy-vitamin D3; TNF-α, tumor necrosis factor-α; RANKL, receptor activator of NF-kappaB ligand; RIP1, receptor-interacting protein 1; TRAF6, TNF receptor-associated factor 6, E3 ubiquitin protein ligase; aPKCs, atypical protein kinase C; UBA, ubiquitin association; IKK, IκB kinase.

  • Fig. 3 Model for the coupling of bone resorption to bone formation in Paget's disease. MVNP expression in pagetic OCL results in high levels of IL-6 that induce ephrinB2 on OCL and EphB4 on osteoblasts to increase coupled bone formation. MVNP also induces IGF1 expression by OCL that further drives bone formation and increases ephrinB2 on OCL. MVNP, measles virus nucleocapsid protein; OCL, osteoclasts; IL-6, interleukin-6; EphB4, EPH receptor B4; IGF1, insulin-like growth factor 1.


Cited by  2 articles

Intravenous Zoledronate for a Patient with Paget's Disease
Ki-Choul Kim
J Bone Metab. 2014;21(3):223-226.    doi: 10.11005/jbm.2014.21.3.223.

Paget's Disease: Skeletal Manifestations and Effect of Bisphosphonates
Ho Kang, Young-Chang Park, Kyu Hyun Yang
J Bone Metab. 2017;24(2):97-103.    doi: 10.11005/jbm.2017.24.2.97.


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