Paget's disease of bone—genetic and environmental factors

Singer, Frederick R.

doi:10.1038/nrendo.2015.138

Cited by 53 publications

(34 citation statements)

References 114 publications

(120 reference statements)

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“…P62 gene mutation was considered to be the main cause of Paget's disease of bone (PDB) [25] , [26] , [27] , [28] , which is a skeletal disorder characterized by osteolytic lesions and overactive osteoclasts. To date, 28 distinct P62 mutations have been reported in PDB patients and the most commonly identified mutation leads to a proline to leucine substitution at residue 392 (P392L) [28] , [68] . Dysregulated expression of P62 protein promotes osteoclastogenesis, bone resorption and osteolytic lesions through the NF-κB activation pathway, leading to focal areas of aberrant and excessive bone turnover of PDB patients [69] .…”

Section: The Role Of P62 In Osteoclastogenesismentioning

confidence: 99%

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P62: An emerging oncotarget for osteolytic metastasis

Zhang

Yang

Dong

2016

Journal of Bone Oncology

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Bone metastasis occurs in the majority of late-stage tumors with poor prognosis. It is mainly classified as osteoblastic metastasis and osteolytic metastasis. The pathogenesis of osteolytic metastasis is a “vicious cycle” between tumor cells and bone cells (primarily the osteoclasts), which is mediated by secretory factors. The P62 adapter protein is a versatile multitasker between tumor cells and bone cells. The overexpression of P62 has been detected among a variety of tumors, playing positive roles in both tumorigenesis and metastasis. Moreover, P62 is an important modulator of the osteoclastogenesis pathway. Therefore, the ability of P62 to modulate tumors and osteoclasts suggests that it may be a feasible oncotarget for bone metastasis, especially for osteolytic metastasis. Recent research has shown that a P62 DNA vaccine triggered effective anti-tumor, anti-metastatic and anti-osteoporotic activities. Growing lines of evidence point to P62 as an emerging oncotarget for osteolytic metastasis. In this review, we outline the different roles of P62 in tumor cells and osteoclasts, focusing on the P62-related signaling pathway in key steps of osteolytic metastasis, including tumorigenesis, metastasis and osteoclastogenesis. Finally, we discuss the newest observations on P62 as an oncotarget for osteolytic metastasis treatment.

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Section: The Role Of P62 In Osteoclastogenesismentioning

confidence: 99%

“…The dysregulated expression of the P62 protein promotes osteoclastogenesis, bone resorption and osteolytic lesions. Therefore, P62 has long been thought of as a promising molecular target in PDB and other bone metabolic diseases [28] .…”

Section: Introductionmentioning

confidence: 99%

P62: An emerging oncotarget for osteolytic metastasis

Zhang

Yang

Dong

2016

Journal of Bone Oncology

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“…Although still controversial, some consider paramyxovirus infection, especially measles virus infection, to be a potential risk factor in PDB development. 9, 10, 11 Recently, a marked decline in the prevalence of PDB in some regions has been noted, a finding that suggests a role for environmental factors in PDB development. 9 …”

Section: Introductionmentioning

confidence: 99%

A FKBP5 mutation is associated with Paget’s disease of bone and enhances osteoclastogenesis

Jiao

Yinchang

et al. 2017

Exp Mol Med

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Paget's disease of bone (PDB) is a common metabolic bone disease that is characterized by aberrant focal bone remodeling, which is caused by excessive osteoclastic bone resorption followed by disorganized osteoblastic bone formation. Genetic factors are a critical determinant of PDB pathogenesis, and several susceptibility genes and loci have been reported, including SQSTM1, TNFSF11A, TNFRSF11B, VCP, OPTN, CSF1 and DCSTAMP. Herein, we report a case of Chinese familial PDB without mutations in known genes and identify a novel c.163G>C (p.Val55Leu) mutation in FKBP5 (encodes FK506-binding protein 51, FKBP51) associated with PDB using whole-exome sequencing. Mutant FKBP51 enhanced the Akt phosphorylation and kinase activity in cells. A study of osteoclast function using FKBP51V55L KI transgenic mice proved that osteoclast precursors from FKBP51V55L mice were hyperresponsive to RANKL, and osteoclasts derived from FKBP51V55L mice displayed more intensive bone resorbing activity than did FKBP51WT controls. The osteoclast-specific molecules tartrate-resistant acid phosphatase, osteoclast-associated receptor and transcription factor NFATC1 were increased in bone marrow-derived monocyte/macrophage cells (BMMs) from FKBP51V55L mice during osteoclast differentiation. However, c-fos expression showed no significant difference in the wild-type and mutant groups. Akt phosphorylation in FKBP51V55L BMMs was elevated in response to RANKL. In contrast, IκB degradation, ERK phosphorylation and LC3II expression showed no difference in wild-type and mutant BMMs. Micro-CT analysis revealed an intensive trabecular bone resorption pattern in FKBP51V55L mice, and suspicious osteolytic bone lesions were noted in three-dimensional reconstruction of distal femurs from mutant mice. These results demonstrate that the mutant FKBP51V55L promotes osteoclastogenesis and function, which could subsequently participate in PDB development.

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“…Additionally, animal-related factors may be important in the etiology of PDB and may interact with SQSTM1 mutations, thus influencing the disease severity [40]. It was reported that the decreasing incidence of Paget's disease, which could be attributed to measles vaccination, supports an etiologic role of the virus [41]. However, RNA of the measles virus was not found in the bone marrow and bone cell cultures isolated from patients with Paget's disease in New Zealand [42].…”

Section: Discussionmentioning

confidence: 99%