Review
Genetics and aetiology of Pagetic disorders of bone

https://doi.org/10.1016/j.abb.2008.02.045Get rights and content

Abstract

Paget’s disease of bone (PDB) is a late-onset disorder characterised by focal areas of increased bone turnover containing enlarged hyperactive osteoclasts. The disease has a strong genetic predisposition and mutations in SQSTM1 have been associated with familial and sporadic disease in up to 40% of cases. Additional genetic loci have been associated in other cases, but genes are yet to be identified. Earlier-onset conditions with similar bone pathology (familial expansile osteolysis, expansile skeletal hyperphosphatasia and early-onset PDB) are caused by mutations in TNFRSF11A (RANK). The syndrome of inclusion body myositis, Paget’s disease and frontotemporal dementia is caused by mutations in VCP. Despite the increased knowledge about genes involved in PDB and related disorders, the etiology of the diseases remains puzzling. Presence of inclusion bodies appears to link Pagetic diseases mechanistically to diseases associated with presence of misfolded proteins or abnormalities in the ubiquitin-proteasomal, or autophagy pathways. Juvenile PDB, caused by osteoprotegerin deficiency, appears mechanistically distinct from the other Pagetic diseases. This review will discuss evidence from recent studies, including new animal models for Pagetic diseases.

Section snippets

Pathophysiology of PDB and related disorders

Paget’s disease of bone (PDB

Genetics and pathogenesis of Juvenile Paget’s disease, or “osteoprotegerin deficiency”

JPD has been shown to be caused by autosomal recessive mutations in the gene for OPG (TNFRSF11B), a member of the tumour necrosis factor (TNF) receptor superfamily, resulting in either complete deletion of the OPG gene [25] or mutations within the gene [26]. OPG is a soluble receptor secreted by osteoblasts [27] and discussed in more detail in the article by Boyce in this issue [137]. It acts as a decoy receptor for receptor activator of nuclear factor kappa B ligand (RANKL) to its receptor

Genetics of late-onset Paget’s disease

A genetic component to PDB has been long-recognised [34], [35], and many families have been documented where PDB is transmitted with an autosomal dominant mode of inheritance. Linkage studies in these families have identified a number of susceptibility loci on chromosomes 6p21 (PDB1) [36], 18q21.1-22 (PDB2) [37], [38], 5q35 (PDB3) [39], [40], 5q31 (PDB4) [39], 2q36 (PDB5) [40], 10p13 (PDB6) [40] and 18q23 (PDB7) [41]. The regions identified are typically large and contain many genes, any number

Genes in early-onset Pagetic diseases

ePDB, FEO and ESH are allelic conditions caused by heterozygous insertion mutations in the signal peptide region of the RANK gene, TNFRSF11A, all of which are predicted to cause lack of signal peptide cleavage of the RANK protein. ePDB is caused by a 27 bp duplication insertion (75dup27) [15], FEO by 18 bp duplications (84dup18 or 83dup18; leading to the addition of the same 6 amino acids) [63], [64] and ESH by a 15 bp duplication (84dup15) [65]. Analysis of the TNFRSF11A secondary DNA structure

Role of SQSTM1

SQSTM1 is a ubiquitously expressed cytoplasmic and nuclear protein that acts as a dimer. It functions as a scaffold protein with multiple domains to integrate kinase-activated and ubiquitin-mediated signalling pathways downstream from multiple receptors [79]. Of particular relevance to bone physiology is the involvement of SQSTM1 with the interleukin receptor and TNF receptor family members, especially RANK. SQSTM1 is known to interact with Src family members, atypical Protein Kinase C members,

Role of VCP

VCP is a ubiquitously expressed member of the type II AAA–ATPase family, with three structural domains. An N-terminal part (CDC48) is involved in ubiquitin binding, whereas two central domains (D1 and D2) bind and hydrolyse ATP. The crystal structure has been resolved [92], [93] and all mutations found in IBMFPD are spatially clustered in pairs in the region where the CDC48 domain interfaces with the D1-ATPase domain [69], suggesting the affected residues are critically involved in a specific

Role of RANK

RANK is the receptor for the critical osteoclast growth factor RANKL. The protein has a restricted expression and besides osteoclast and their precursors is found only on dendritic cells, B and T cells, chondrocytes, mammary epithelial cells and fibroblasts. Boyce and coworkers describe the RANK/RANKL axis in detail in an accompanying paper in this issue [137]. RANK and RANKL are absolutely critical in osteoclast development illustrated by the fact that knockout mice for either gene are

Inclusion bodies

A pathognomic feature found in all Pagetic diseases is the presence of inclusion bodies in osteoclasts within the affected areas of the bone, both in the nucleus as well as in the cytoplasm. Not all osteoclasts contain these inclusions and in those that do, not all nuclei are affected. Inclusions are not found in any other cell type in bone. Ultrastructural examination is required to fully appreciate these inclusions which in Pagetic diseases typically present as highly ordered paracrystalline

Effects of mutations in Pagetic genes in cells and animal models

Despite the increased knowledge about genes involved in PDB and related disorders, the etiology of the diseases remain unclear. The cellular effects of the mutations found in SQSTM1, VCP and TNFRSF11A have recently been investigated in in vitro systems, but results so far are not conclusive. The first knock-in animal models for Pagetic diseases have now been generated in the expectation that in a proper physiological context such animals may show all the hallmarks of the human conditions. Data

Etiology of Pagetic diseases

How can the bone pathology seen in the various forms of Pagetic diseases be explained by the genetic and cellular data available? It is interesting to note that all mutations identified occur in proteins that function as oligomers, which is necessary in order for heterozygous mutations to exert dominant effects. There is no clear overall hypothesis that explains all the pathological findings in patients, but there are now some hints as to the mechanisms that may be affected through knowledge of

Conclusion

There has been enormous progress over the past years in elucidating genetic factors in Pagetic diseases, but there are additional loci in which predisposing genes remain to be found. Studies on the effects of mutant proteins have yielded conflicting results, and few have been conducted in the appropriate heterozygous context. Animal models for PDB and for ePDB have been generated and some show bone pathology similar to the human disease. The similarities between Pagetic diseases and other

Acknowledgments

The authors thank their colleagues and students for supplying illustrations for this paper, especially Debbie Scott for Fig. 1, Fig. 2, Fig. 3, Fig. 5; Samuel Yuen for Fig. 4 and David Mellis and John Greenhorn for Fig. 6. We are grateful for discussions on the topic of Pagetic diseases with Dr. Julie Crockett and Prof. Mike Rogers. Our research in this area has been funded by the Arthritis Research Campaign (grant R0616) and the National Association for the Relief of Paget’s disease. L.J.H. is

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