Premium
Experimental Models of Paget's Disease
Author(s) -
Kurihara Noriyoshi,
Zhou Hua,
Reddy Sakamuri V,
Garcia Palacios Veronica,
Subler Mark A,
Dempster David W,
Windle Jolene J,
Roodman G David
Publication year - 2006
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.06s210
Subject(s) - bone resorption , cancellous bone , osteoblast , rankl , resorption , bone disease , genetically modified mouse , osteoclast , bone remodeling , transgene , pathology , endocrinology , chemistry , medicine , cancer research , osteoporosis , biology , in vitro , gene , receptor , genetics , activator (genetics)
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) 2 D 3 , RANKL, and TNF‐α; increased expression of the TAF II ‐ 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) 2 D 3 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.