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) 2 D 3 , RANKL, and TNF-␣; 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 ‫ס‬ 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.

Role of NF-κB in the skeleton

“…Knock-in mice bearing a PD p62 mutation (P394L) have OCs with increased responsivity to RANKL and low bone mass, but lack the focal lesions and hypersensitivity to vitamin D3 seen in human PD [87], suggesting that other factors are required for PD. The measles protein, MVNP, when expressed in OC precursors, recapitulates the PD features such as focal lesions and hypersensitivity to vitamin D3, which is not produced by p62 mutation [88], but there is no evidence that these effects are mediated by NF-κB.…”

Total shoulder arthroplasty in a patient with Paget’s Disease: case report and review of the literature

“…The specific etiology of Paget's Disease remains unclear and is a source of controversy; various authors have proposed genetic, environmental, 15,16,34 and infectious 6,7,13,19,27 pathophysiologic theories as to the source of the disease, with no consensus as to which is most accurate. Regardless of the etiology, Paget's Disease demonstrates characteristic clinical and radiographic features.…”

Paget’s disease: Epidemiology and pathophysiology

“…Kurihara et al [43] developed a successful animal model of Paget's disease using transgenic mice in which the MVNP was targeted to cells in the osteoclast lineage. Selby et al [44] showed in in vitro studies that CDV induces osteoclastogenesis in human osteoclast precursors.…”