IBMS BoneKEy | Perspective

The role of genes in the pathogenesis of Paget's disease of bone

Pui Yan Jenny Chung
Wim Van Hul



Paget's disease of bone (PDB) is the second most common metabolic bone disease in the Western world after osteoporosis. Although not always recognized in the early years, genetic factors do contribute to the pathogenesis of PDB in at least a subset of patients. This review summarizes how the current understanding of the role of genes in this condition was obtained, discusses what can be learned from that process, and outlines remaining questions. The first insights were gained by studying monogenic conditions that to some extent resemble the pathogenic mechanisms of increased bone turnover seen in PDB patients. With the involvement, in these conditions, of the genes encoding the OPG and RANK proteins, the importance of the NFκB pathway was solidified. This was also underscored by genetic association studies indicating an effect of genetic variance within TNFRSF11B (OPG) and TNFRSF11A (RANK) on the susceptibility for PDB. Genetic linkage studies in multicase PDB families suggested up to 7 loci but, most likely, most of these will be false positive gene localizations. At present, only one gene, SQSTM1 encoding p62, has been identified by this approach. Together with the VCP gene encoding the valosine-containing protein and being identified as causative for a syndromal form of PDB, the evidence seems to support a pathogenic mechanism caused by increased NFκB signaling. However, more recent functional studies have suggested a more complex situation. The role of both p62 and VCP in the processes of protein degradation, and especially autophagy, indicates that disturbance of these might contribute to the pathogenic mechanisms in PDB. This hypothesis might also be linked with the observation of cellular inclusion bodies in some PDB patients and the hypothesis that these might be due to paramyxovirus infection. Much progress has been made in unraveling the genetic factors involved in PDB but questions such as the tissue-specific and focal aspect of the disease, as well as the observation of a declining prevalence, remain open, making further research of interest. Ongoing genome-wide association studies will definitely contribute to the further unraveling of the pathogenesis of PDB.

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