Paget disease of bone

Abstract

Paget disease of bone (PD) is characterized by excessive bone resorption in focal areas followed by abundant new bone formation, with eventual replacement of the normal bone marrow by vascular and fibrous tissue. The etiology of PD is not well understood, but one PD-linked gene and several other susceptibility loci have been identified, and paramyxoviral gene products have been detected in pagetic osteoclasts. In this review, the pathophysiology of PD and evidence for both a genetic and a viral etiology for PD will be discussed.

Figure 1

Signaling pathways involved in osteoclast formation and activity. When RANKL binds RANK, multiple signaling pathways can be activated, including NF-κB, AKT, JNK, p38 MAPK, and ERK, resulting in subsequent activation of genes that regulate osteoclast formation, bone resorption, and survival. TRAF6 appears to play a central role in the activation of most of these pathways. AP1, activator protein 1; aPKC, atypical PKC; IκB, inhibitor of κB; ASK1, apoptosis signal–regulating kinase 1; BAD, Bcl-2–associated death promoter; IL-1R, IL-1 receptor; IKKα, IκB kinase α; IRAK, IL-1 receptor–associated kinase; JNKK, JNK kinase; MEK, MAPK/ERK kinase; MITF, microphthalmia transcription factor; MKK, MAPK kinase; NFATc₁, nuclear factor of activated T cells cytoplasmic 1; PDK1, phosphoinositide-dependent protein kinase 1; RIP, receptor interacting protein; TNFR1, TNF receptor 1; TRADD, TNF receptor 1–associated death domain.

Figure 2

Normal and pagetic bone. Normal (A) and pagetic (B) bone are shown under polarized light. Pagetic bone is poorly organized and very chaotic in structure and forms “a mosaic pattern.” In contrast, normal bone is highly organized with a lamellar structure. Figure reproduced with permission from The Paget’s Foundation for Paget’s Disease of Bone Related Disorders.

Figure 3

Osteoclasts in normal bone and in Paget’s disease. (A) Normal osteoclasts are large multinucleated cells that contain between 3 and 20 nuclei per cell. (B) In contrast, pagetic osteoclasts are markedly increased in number and size and can contain up to 100 nuclei (arrow). (C) On ultrastructural examination, pagetic osteoclasts have characteristic nuclear (arrowhead) and occasional cytoplasmic inclusions containing paracrystalline arrays that are similar to paramyxoviral nucleocapsids.

Figure 4

Structure of the p62 protein. The blocks indicate domains that mediate association with other proteins or are hypothesized to mediate these associations based upon homology with other proteins. The solid lines below the protein indicate stretches of sequence identity (of 20 amino acids or more) among the mouse, rat, and human p62 proteins. The arrows above the protein indicate the Paget disease-associated mutations identified to date. The splice donor and stop mutations result in a truncated protein lacking the UBA domain. PEST denotes hydrophobic regions that target proteins for rapid degradation (P, proline; E, glutaric acid; S, serine; T, threonine).

Figure 5

A proposed model for the pathogenesis of PD. Mutations that enhance basal osteoclastogenesis predispose patients to PD by creating a permissive environment for its development. A second factor, such as expression of certain viral proteins, may further alter signaling pathways or expression of specific transcription factors, resulting in the abnormal characteristics of pagetic osteoclasts. For example, the increased sensitivity of osteoclast precursors to low levels of 1,25-(OH)₂D₃ and RANKL (RL) enhances osteoclast formation. Further, the increased numbers of osteoclasts would secrete high levels of IL-6, which would further enhance osteoclast formation. Since osteoclast and osteoblast activity remain coupled in PD, the increased osteoclast activity would result in increased osteoblast numbers and rapid formation of new bone. The increased numbers of immature osteoblasts expressing high levels of RANKL and M-CSF would further increase osteoclast formation. As more and more bone is formed, the lesion would eventually become sclerotic.