Osteoclasts expressing the measles virus nucleocapsid gene display a pagetic phenotype

Kurihara, Noriyoshi; Reddy, Sakamuri V.; Menaa, Cheikh; Anderson, D. C.; Roodman, G. David

doi:10.1172/jci8489

Cited by 138 publications

(115 citation statements)

References 27 publications

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“…To date, the nature of the possible environmental trigger remains unknown, but several reports suggested that viral infections of the paramyxovirus family may infect the osteoclast, inducing most of the cellular abnormalities of PDB. (32,33,(47)(48)(49) Indeed, in one of these studies, canine distemper virus not only induced NFkB activation and bone resorption but also markedly increased sequestosome 1/p62 gene expression in human osteoclast cells. (33) Finally, results from our analysis evidenced an increased occurrence of the P392 mutation with the H 2 than H 1 haplotypes.…”

Section: Discussionmentioning

confidence: 96%

SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone

Gennari

Gianfrancesco

Stefano

et al. 2010

Journal of Bone and Mineral Research

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Even though SQSTM1 gene mutations have been identified in a consistent number of patients, the etiology of Paget's disease of bone (PDB) remains in part unknown. In this study we analyzed SQSTM1 mutations in 533 of 608 consecutive PDB patients from several regions, including the high-prevalence area of Campania (also characterized by increased severity of PDB, higher number of familial cases, and peculiar phenotypic characteristics as giant cell tumor). Eleven different mutations (Y383X, P387L, P392L, E396X, M401V, M404V, G411S, D423X, G425E, G425R, and A427D) were observed in 34 of 92 (37%) and 43 of 441 (10%) of familial and sporadic PDB patients, respectively. All five patients with giant cell tumor complicating familial PDB were negative for SQSTM1 mutations. An increased heterogeneity and a different distribution of mutations were observed in southern Italy (showing 9 of the 11 mutations) than in central and northern Italy. Genotype-phenotype analysis showed only a modest reduction in age at diagnosis in patients with truncating versus missense mutations, whereas the number of affected skeletal sites did not differ significantly. Patients from Campania had the highest prevalence of animal contacts (i.e., working or living on a farm or pet ownership) without any difference between patients with or without mutation. However, when familial cases from Campania were considered, animal contacts were observed in 90% of families without mutations. Interestingly, a progressive age-related decrease in the prevalence of animal contacts, as well as a parallel increase in the prevalence of SQSTM1 mutations, was observed in most regions except in the subgroup of patients from Campania. Moreover, patients reporting animal contacts showed an increased number of affected sites (2.54 AE 2.0 versus 2.19 AE 1.9, p < .05) over patients without animal contacts. This difference also was evidenced in the subgroup of patients with SQSTM1 mutations (3.84 AE 2.5 versus 2.76 AE 2.2, p < .05). Overall, these data suggest that animal-related factors may be important in the etiology of PDB and may interact with SQSTM1 mutations in influencing disease severity. ß

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Section: Discussionmentioning

confidence: 96%

SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone

Gennari

Gianfrancesco

Stefano

et al. 2010

Journal of Bone and Mineral Research

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“…Previously, we have demonstrated that other measles virus genes such as matrix protein does not induce pagetic osteoclast development in bone marrow cultures. 4 However, MVNP has been shown to induce NF-kB activation, which may be a potential mechanism in the upregulation of CXCL5 expression in PDB. 4,31 MVNP has been shown to increase gene expressions of other cytokines such as IL-6, FGF-2 and NFATc1, NF-kB transcription factors that may have both direct and indirect effects on pagetic osteoclast development.…”

Section: Discussionmentioning

confidence: 99%

“…4 However, MVNP has been shown to induce NF-kB activation, which may be a potential mechanism in the upregulation of CXCL5 expression in PDB. 4,31 MVNP has been shown to increase gene expressions of other cytokines such as IL-6, FGF-2 and NFATc1, NF-kB transcription factors that may have both direct and indirect effects on pagetic osteoclast development. Therefore, regulatory mechanisms associated with pagetic osteoclast development are complex.…”

Section: Discussionmentioning

confidence: 99%

“…Retroviral supernatants from the producer cell cultures were collected and filtered (0.45 mm pore diameter) for immediate use. Human bone marrow-derived mononuclear cells were transduced with EV or MVNP retroviral supernatants (20%) in the presence of polybrene (4 mg/ml) for 48 h. 4 Enzyme-Linked Immunosorbent Assay (ELISA) CXCL5 in serum samples from age-matched normal subjects, patients with PDB (mean age 70±10) and conditioned media (CM) collected from MVNP-transduced human bone marrow-derived mononuclear cells was assayed by ELISA using anti-CXCL5 antibody. All the PDB patients had either mono-or polyostotic with elevated levels of alkaline phosphatase activity.…”

Section: Mvnp Retroviral Expressionmentioning

confidence: 99%

“…3 We have previously detected the expression of measles virus nucleocapsid (MVNP) transcripts in OCL from patients with PDB. 4 Moreover, the expression of MVNP in OCL precursors develops pagetic OCL in mice. 5 Receptor activator for nuclear factor-kB ligand (RANKL) is expressed by marrow stromal/osteoblast cells in response to several osteotropic factors such as 1,25 dihydroxy vitamin D 3 , parathyroid hormone (PTH), prostaglandin E 2 and interleukin 1b (IL-1b).…”

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CXCL5 stimulation of RANK ligand expression in Paget's disease of bone

Sundaram¹,

Rao

Ries

et al. 2013

Laboratory Investigation

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Paget's disease of bone (PDB) is a chronic focal skeletal disorder that affects 2-3% of the population over 55 years of age. PDB is marked by highly localized areas of bone turnover with increased osteoclast activity. Evidence suggests a functional role for measles virus nucleocapsid protein (MVNP) in the pathogenesis of PDB. In the present study, we identified elevated levels (B180-fold) of CXCL5 mRNA expression in bone marrow cells from patients with PDB compared with that in normal subjects. In addition, CXCL5 levels are increased (five-fold) in serum samples from patients with PDB. Furthermore, MVNP transduction in human bone marrow monocytes significantly increased CXCL5 mRNA expression. Realtime PCR analysis showed that CXCL5 stimulation increased (6.8-fold) RANKL mRNA expression in normal human bone marrow-derived stromal (SAKA-T) cells. Moreover, CXCL5 increased (5.2-fold) CXCR1 receptor expression in these cells. We further showed that CXCL5 treatment elevated the expression levels of phospho-ERK1/2 and phospho-p38. CXCL5 also significantly increased phosphorylation of CREB (cAMP response element-binding) in bone marrow stromal/preosteoblast cells. Chromatin immuneprecipitation (ChIP) assay confirmed phospho-CREB binding to RANKL gene promoter region. Further, the suppression of p-CREB expression by the inhibitors of ERK1/2, p38 and PKA significantly decreased CXCL5 stimulation of hRANKL gene promoter activity. Thus, our results suggest that CREB is a downstream effector of CXCL5 signaling and that increased levels of CXCL5 contribute to enhanced levels of RANKL expression in PDB. Paget's disease of bone (PDB) is characterized by highly localized areas of bone turnover with increased osteoclast (OCL) activity followed by poor quality new bone formation due to an exaggerated osteoblast response. Approximately 1% of patients with PDB develop osteosarcoma. 1 PDB is inherited as an autosomal dominant trait with genetic heterogeneity and affects 2-3% of the population over the age of 55 years. Both genetic and environmental factors are involved in the pathogenesis of PDB. Mutations in the ubiquitin-associated domain of sequestosome 1 (SQSTM1/p62) have been identified at 40% in familial and 10% in sporadic cases. 2 Environmental factors such as paramyxoviruses are implicated in PDB. 3 We have previously detected the expression of measles virus nucleocapsid (MVNP) transcripts in OCL from patients with PDB. 4 Moreover, the expression of MVNP in OCL precursors develops pagetic OCL in mice. 5 Receptor activator for nuclear factor-kB ligand (RANKL) is expressed by marrow stromal/osteoblast cells in response to several osteotropic factors such as 1,25 dihydroxy vitamin D 3 , parathyroid hormone (PTH), prostaglandin E 2 and interleukin 1b (IL-1b). 6-8 RANKL-RANK signaling is critical for osteoclast differentiation/bone resorption activity. Enhanced levels of RANKL are associated with PDB. 9,10 In addition, elevated levels of IL-6, macrophage colony-stimulating factor (M-CSF) and endothelin-1 have been reported in PD...

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Chapter 72. Paget's Disease of Bone

Siris¹,

Roodman²

2008

Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism

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Osteoclasts expressing the measles virus nucleocapsid gene display a pagetic phenotype

Cited by 138 publications

References 27 publications

SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone

SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone

CXCL5 stimulation of RANK ligand expression in Paget's disease of bone

Chapter 72. Paget's Disease of Bone

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