Molecular Genetics of Paget's Disease of Bone

Abstract

Paget's disease of bone (PDB) is a chronic disorder of bone metabolism, which typically results in enlarged and deformed bones in one or more regions of the skeleton. The aetiology of PDB has remained unknown for several decades, but either environmental or genetic factors have been implicated. The former mainly concern the presence of a slow‐acting viral infection, a condition that may be present for many years before symptoms appear. However, there are also several data supporting a hereditary hypothesis, since in up to 40% of patients the disease may appear in more than one family member. The genetic architecture of PDB is incompletely understood, but recent evidence suggests that the disease may be caused by a combination of rare variants in genes such as SQSTM1 (detected in up to 50% of familial cases of PDB) and more common variants (i.e. polymorphisms) in genes such as CSF1, TNFRSF11A, OPTN and TM7SF4.

Key Concepts:

  • Paget's disease of bone (PDB) is a focal disorder of bone metabolism characterised by enlarged and deformed bones in one (monostotic form) or more regions (polyostotic form) of the skeleton.

  • Over the last two decades there have been major advances in our understanding of the genetic basis of the disorder. Mutations in 3 genes have been detected in rare syndromes related to PDB and mutations in SQSTM1 gene have been associated with the classical form of PDB in up to 50% of familial cases.

  • SQSTM1 gene encodes for the p62/sequestosome 1 protein, which acts as a scaffold protein in the NFκB pathway as well as an intermediate protein in the proteosomal degradation of polyubiquitinated proteins.

  • To date the exact molecular mechanisms leading to the development of pagetic lesions in SQSTM1 mutation carriers remain to be defined. Indeed, recent experimental evidence suggests that additional contribution from environmental factors (i.e. a viral infection with paramyxovirus) or other genetic factors (i.e. polymorphisms) may be required to induce the full pagetic phenotype in the presence of SQSTM1 mutation.

  • The genetic cause of PDB in familial cases negative for SQSTM1 mutations remains to be determined in more detail.

Keywords: Paget's disease of bone; p62/sequestosome; bone metabolism; genetics; NFκB signalling

Figure 1.

Bone histology in Paget's disease. (a) Typical histological features showing increased bone resorption by large and hyper‐multinucleated osteoclasts; (b) poorly organised and very chaotic structure of Pagetic bone under polarised light, showing the typical ‘mosaic pattern (or woven bone)’ instead of lamellar bone tissue.

Figure 2.

Genetic alterations of components of the NFκB pathway and its interacting proteins in PDB and related syndromes. Activating mutations of RANK cause FEO, ESH and early‐onset PDB. Mutations affecting the p62/sequestosome 1 protein have been identified in classic PDB. Mutations in OPG gene (TNFRSF11B) leading to OPG deficiency results in JPD. Mutations in VCP cause the syndrome of hereditary IBMPFD.

Figure 3.

Structure and functional domains of the p62/SQSTM1 protein. This protein has numerous domains: a Phox and Bem1p (PB1) domain, an atypical zinc finger (ZZ), two nuclear localisation signals (NLS1 and NLS2), a p38 binding sequence (p38BS), a Lim protein binding region (LB), a TRAF6 binding sequence (TBS), 2 PEST sequences (P1 and P2), a nuclear export signal (NES), a LC3‐interacting region (LIR), a KIR domain and a C‐terminal UBA domain. The SQSTM1 gene mutations associated with PDB and their position within the p62 protein are indicated in black (UBA domain mutations) or red (mutations outside the UBA domain), respectively.

Figure 4.

Proposed mechanism linking most (but not all) PDB‐associated mutations of p62 with increased NFκB signalling. (a) Under normal conditions the deubiquinating enzyme CYLD is recruited by the UBA domain of p62 to the intracellular domain of the RANK receptor, where it deubiquitinates TRAF6, leading to inhibition of RANK signalling; (b) the presence of mutated p62 proteins (i.e. due to P392L mutation) impairs the recruitment of CYLD and increases TRAF6 activity which results in enhanced RANK signalling and osteoclast activation.

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Further Reading

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Zhu G, Wu CJ, Zhao Y and Ashwell JD (2007) Optineurin negatively regulates TNFalpha‐ induced NF‐kappaB activation by competing with NEMO for ubiquitinated RIP. Current Biology 17(16): 1438–1443.

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Gennari, Luigi, Gianfrancesco, Fernando, Rendina, Domenico, and Merlotti, Daniela(Jul 2014) Molecular Genetics of Paget's Disease of Bone. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024396]