Experimental models of Paget's disease

Noriyoshi Kurihara, Hua Zhou, Sakamuri V. Reddy, Veronica Garcia Palacios, Mark A. Subler, David W. Dempster, Jolene J. Windle, G. David Roodman

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

We targeted the MVNP gene to the OCL lineage in transgenic mice. These mice developed abnormal OCLs and bone lesions similar to those found in Paget's patients. These results show that persistent expression of MVNP in OCLs can induce pagetic-like bone lesions in vivo. Introduction: Paget's disease (PD) is one of the most exaggerated examples of abnormal bone remodeling, with increased bone resorption and excessive new bone formation. However, its etiology is unclear. A viral etiology for PD has been suggested based on the presence of paramyxoviral-like nuclear inclusions, detection of measles virus nucleocapsid (MVNP) mRNA or protein in osteoclasts (OCLs) from PD lesions, and in vitro studies showing that transfection of normal OCL precursors with the MVNP gene results in formation of OCLs that express a pagetic phenotype (increased numbers of OCLs; increased responsivity to 1,25(OH)2D3, RANKL, and TNF-α; increased expression of the TAFII-17 gene, and increased bone resorption capacity). Materials and Methods: We targeted MVNP to cells in the OCL lineage in transgenic mice using the TRACP promoter. Results: Histomorphometric analysis showed that there was a 64% increase in OCL perimeter (p = 6.0002) and 37% increase in osteoblast (OBL) perimeter in MVNP mice. In a mouse that was 14 months of age, there was a 225% increase in OBL perimeter and 149% in OBL perimeter. This was accompanied by increased cancellous bone volume (83%) and trabecular width (47%) and number (25%), with a marked increase in the amount of woven bone. In contrast, cancellous bone volume decreased between 3 and 12 months in wildtype (WT) mice, whereas cancellous bone volume in MVNP mice increased over the same time period. Ex vivo studies showed that the numbers of OCLs formed in marrow cultures from MVNP mice were increased, and the OCLs were hyper-responsive to 1,25(OH)2D3 and had an increased bone resorbing capacity compared with WT cultures. Conclusion: These results show that expression of MVNP in OCL in vivo results in a bone phenotype that is characteristic of PD.

Original languageEnglish (US)
JournalJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Volume21
Issue numberSUPPL. 2
DOIs
StatePublished - Dec 2006
Externally publishedYes

Fingerprint

Osteoclasts
Nucleocapsid
Measles virus
Theoretical Models
Bone and Bones
Osteoblasts
Bone Resorption
Transgenic Mice
Genes
Phenotype
Intranuclear Inclusion Bodies
Bone Remodeling
Osteogenesis
Transfection
Bone Marrow

Keywords

  • IL-6
  • measles virus nucleocapsid
  • osteoclast
  • Paget's disease
  • TAF-17

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism
  • Surgery

Cite this

Experimental models of Paget's disease. / Kurihara, Noriyoshi; Zhou, Hua; Reddy, Sakamuri V.; Garcia Palacios, Veronica; Subler, Mark A.; Dempster, David W.; Windle, Jolene J.; Roodman, G. David.

In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Vol. 21, No. SUPPL. 2, 12.2006.

Research output: Contribution to journalArticle

Kurihara, Noriyoshi ; Zhou, Hua ; Reddy, Sakamuri V. ; Garcia Palacios, Veronica ; Subler, Mark A. ; Dempster, David W. ; Windle, Jolene J. ; Roodman, G. David. / Experimental models of Paget's disease. In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2006 ; Vol. 21, No. SUPPL. 2.
@article{6c61e35a82fa4f9295ef9c0be70073ba,
title = "Experimental models of Paget's disease",
abstract = "We targeted the MVNP gene to the OCL lineage in transgenic mice. These mice developed abnormal OCLs and bone lesions similar to those found in Paget's patients. These results show that persistent expression of MVNP in OCLs can induce pagetic-like bone lesions in vivo. Introduction: Paget's disease (PD) is one of the most exaggerated examples of abnormal bone remodeling, with increased bone resorption and excessive new bone formation. However, its etiology is unclear. A viral etiology for PD has been suggested based on the presence of paramyxoviral-like nuclear inclusions, detection of measles virus nucleocapsid (MVNP) mRNA or protein in osteoclasts (OCLs) from PD lesions, and in vitro studies showing that transfection of normal OCL precursors with the MVNP gene results in formation of OCLs that express a pagetic phenotype (increased numbers of OCLs; increased responsivity to 1,25(OH)2D3, RANKL, and TNF-α; increased expression of the TAFII-17 gene, and increased bone resorption capacity). Materials and Methods: We targeted MVNP to cells in the OCL lineage in transgenic mice using the TRACP promoter. Results: Histomorphometric analysis showed that there was a 64{\%} increase in OCL perimeter (p = 6.0002) and 37{\%} increase in osteoblast (OBL) perimeter in MVNP mice. In a mouse that was 14 months of age, there was a 225{\%} increase in OBL perimeter and 149{\%} in OBL perimeter. This was accompanied by increased cancellous bone volume (83{\%}) and trabecular width (47{\%}) and number (25{\%}), with a marked increase in the amount of woven bone. In contrast, cancellous bone volume decreased between 3 and 12 months in wildtype (WT) mice, whereas cancellous bone volume in MVNP mice increased over the same time period. Ex vivo studies showed that the numbers of OCLs formed in marrow cultures from MVNP mice were increased, and the OCLs were hyper-responsive to 1,25(OH)2D3 and had an increased bone resorbing capacity compared with WT cultures. Conclusion: These results show that expression of MVNP in OCL in vivo results in a bone phenotype that is characteristic of PD.",
keywords = "IL-6, measles virus nucleocapsid, osteoclast, Paget's disease, TAF-17",
author = "Noriyoshi Kurihara and Hua Zhou and Reddy, {Sakamuri V.} and {Garcia Palacios}, Veronica and Subler, {Mark A.} and Dempster, {David W.} and Windle, {Jolene J.} and Roodman, {G. David}",
year = "2006",
month = "12",
doi = "10.1359/jbmr.06s210",
language = "English (US)",
volume = "21",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",
number = "SUPPL. 2",

}

TY - JOUR

T1 - Experimental models of Paget's disease

AU - Kurihara, Noriyoshi

AU - Zhou, Hua

AU - Reddy, Sakamuri V.

AU - Garcia Palacios, Veronica

AU - Subler, Mark A.

AU - Dempster, David W.

AU - Windle, Jolene J.

AU - Roodman, G. David

PY - 2006/12

Y1 - 2006/12

N2 - We targeted the MVNP gene to the OCL lineage in transgenic mice. These mice developed abnormal OCLs and bone lesions similar to those found in Paget's patients. These results show that persistent expression of MVNP in OCLs can induce pagetic-like bone lesions in vivo. Introduction: Paget's disease (PD) is one of the most exaggerated examples of abnormal bone remodeling, with increased bone resorption and excessive new bone formation. However, its etiology is unclear. A viral etiology for PD has been suggested based on the presence of paramyxoviral-like nuclear inclusions, detection of measles virus nucleocapsid (MVNP) mRNA or protein in osteoclasts (OCLs) from PD lesions, and in vitro studies showing that transfection of normal OCL precursors with the MVNP gene results in formation of OCLs that express a pagetic phenotype (increased numbers of OCLs; increased responsivity to 1,25(OH)2D3, RANKL, and TNF-α; increased expression of the TAFII-17 gene, and increased bone resorption capacity). Materials and Methods: We targeted MVNP to cells in the OCL lineage in transgenic mice using the TRACP promoter. Results: Histomorphometric analysis showed that there was a 64% increase in OCL perimeter (p = 6.0002) and 37% increase in osteoblast (OBL) perimeter in MVNP mice. In a mouse that was 14 months of age, there was a 225% increase in OBL perimeter and 149% in OBL perimeter. This was accompanied by increased cancellous bone volume (83%) and trabecular width (47%) and number (25%), with a marked increase in the amount of woven bone. In contrast, cancellous bone volume decreased between 3 and 12 months in wildtype (WT) mice, whereas cancellous bone volume in MVNP mice increased over the same time period. Ex vivo studies showed that the numbers of OCLs formed in marrow cultures from MVNP mice were increased, and the OCLs were hyper-responsive to 1,25(OH)2D3 and had an increased bone resorbing capacity compared with WT cultures. Conclusion: These results show that expression of MVNP in OCL in vivo results in a bone phenotype that is characteristic of PD.

AB - We targeted the MVNP gene to the OCL lineage in transgenic mice. These mice developed abnormal OCLs and bone lesions similar to those found in Paget's patients. These results show that persistent expression of MVNP in OCLs can induce pagetic-like bone lesions in vivo. Introduction: Paget's disease (PD) is one of the most exaggerated examples of abnormal bone remodeling, with increased bone resorption and excessive new bone formation. However, its etiology is unclear. A viral etiology for PD has been suggested based on the presence of paramyxoviral-like nuclear inclusions, detection of measles virus nucleocapsid (MVNP) mRNA or protein in osteoclasts (OCLs) from PD lesions, and in vitro studies showing that transfection of normal OCL precursors with the MVNP gene results in formation of OCLs that express a pagetic phenotype (increased numbers of OCLs; increased responsivity to 1,25(OH)2D3, RANKL, and TNF-α; increased expression of the TAFII-17 gene, and increased bone resorption capacity). Materials and Methods: We targeted MVNP to cells in the OCL lineage in transgenic mice using the TRACP promoter. Results: Histomorphometric analysis showed that there was a 64% increase in OCL perimeter (p = 6.0002) and 37% increase in osteoblast (OBL) perimeter in MVNP mice. In a mouse that was 14 months of age, there was a 225% increase in OBL perimeter and 149% in OBL perimeter. This was accompanied by increased cancellous bone volume (83%) and trabecular width (47%) and number (25%), with a marked increase in the amount of woven bone. In contrast, cancellous bone volume decreased between 3 and 12 months in wildtype (WT) mice, whereas cancellous bone volume in MVNP mice increased over the same time period. Ex vivo studies showed that the numbers of OCLs formed in marrow cultures from MVNP mice were increased, and the OCLs were hyper-responsive to 1,25(OH)2D3 and had an increased bone resorbing capacity compared with WT cultures. Conclusion: These results show that expression of MVNP in OCL in vivo results in a bone phenotype that is characteristic of PD.

KW - IL-6

KW - measles virus nucleocapsid

KW - osteoclast

KW - Paget's disease

KW - TAF-17

UR - http://www.scopus.com/inward/record.url?scp=34247848056&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34247848056&partnerID=8YFLogxK

U2 - 10.1359/jbmr.06s210

DO - 10.1359/jbmr.06s210

M3 - Article

C2 - 17229020

AN - SCOPUS:34247848056

VL - 21

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - SUPPL. 2

ER -