Pathogenesis of Paget Disease of Bone

Abstract

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’s sarcoma of the patella

“…Osteoclasts in PDB are large with up to 100 nuclei. They are derived from monocytes/macrophages under the influence of a variety of transcription factors and osteoclast precursors from PDB patients have increased sensitivity to the major transcription factor RANKL in vitro [40].…”

“…A family history pertains in 15 %, which appears to be autosomal dominant with incomplete penetrance. In first-degree relatives, there is a seven to tenfold increase in the incidence of the disease [1,3,40,41]. Genetic predisposition to PDB appears to be regulated by variants in several genes involved in the differentiation and maturation of osteoclasts.…”

“…SQSTM1 gene mutations, most involving the ubiquitin binding domain, occur in 40-50 % of familial PDB and in about 5-10 % of individuals with sporadic PDB. The protein product is p62 (sequestrome 1), which affects regulation of RANK L-mediated activation of NF-β, which has a major role in osteoclast function [3,40,[42][43][44][45][46]. Although there are some genotype phenotype relationships [45,46], the severity of the disease appears to be diminishing despite the presence of mutations and not all individuals with mutations get PDB [40].…”

“…It has been suggested that variant mutations of these alternate genes may pertain in adult PDB in which SQSTM mutations are absent. Although individually these cause no disease, combinations of such mutations may predispose to an increased risk of PDB due to dysregulation of osteoclasts [40].…”

“…Evidence for a viral cause and persistence of infection remains conflicting and controversial. Paramyxovirus viral proteins can modulate osteoclasts and there appears to be a subset of patients who have persistent measles virus nucleocapsid protein [1,3,40].…”