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Sequence analysis of measles virus nucleocapsid transcripts in patients with Paget's disease
William E Friedrichs1, Sakamuri V Reddy, Jan M Bruder
1Department of Medicine/Hematology, University of Texas Health Science Center, San Antonio, USA.
Abstract:
It has been debated for almost 30 years whether Paget's disease of bone results from paramyxoviral infection of osteoclasts (OCs). Paramyxoviral-like nuclear inclusions are found in OCs from patients with Paget's disease, and measles virus (MV) or canine distemper virus (CDV) messenger RNA (mRNA) transcripts have been detected by in situ hybridization in bone cells from pagetic lesions. Furthermore, immunocytochemical studies have shown the presence of several paramyxoviral species in OCs from patients with Paget's disease. However, others have been unable to detect paramyxoviral transcripts in bone samples from patients with Paget's disease or marrow cultures from involved sites of patients with Paget's disease. Furthermore, no one has been able to isolate an infectious virus from pagetic bone samples or marrow cells from patients with Paget's disease, and a full-length viral gene has not been sequenced from pagetic samples. In this study, we have obtained the full-length sequence for the MV nucleocapsid (MVNP) gene in bone marrow from an involved site from a patient with Paget's disease and more than 700 base pairs (bps) of MVNP sequence in 3 other patients with Paget's disease. These sequences were undetectable in four normal marrow samples studied simultaneously. The sequences from the patients contained multiple mutations that differed from the Edmonston strain MVNP gene. These findings are consistent with the presence of a chronic MV infection in affected sites from these patients with Paget's disease.
Insights
Paget's disease of bone may be caused by a chronic measles virus (MV) infection. This study found unique MV nucleocapsid gene sequences in bone marrow from Paget's disease patients, not in healthy individuals.
Area of Science:
- Virology
- Bone Biology
- Genetics
Background:
- Paget's disease of bone etiology remains debated, with paramyxoviral infection of osteoclasts a long-standing hypothesis.
- Previous studies reported paramyxoviral inclusions and RNA in pagetic bone cells, but failed to isolate infectious virus or sequence full viral genes.
- Conflicting findings highlight the need for definitive evidence linking viruses to Paget's disease.
Purpose of the Study:
- To investigate the presence and genetic characteristics of measles virus (MV) in bone marrow from patients with Paget's disease.
- To compare viral sequences found in affected patients with those in healthy controls.
- To provide molecular evidence supporting or refuting the viral hypothesis of Paget's disease.
Main Methods:
- Nucleic acid sequencing to obtain the full-length MV nucleocapsid (MVNP) gene sequence from bone marrow of Paget's disease patients.
- Detection and sequencing of MVNP gene fragments (over 700 base pairs) in additional patients.
- Comparative analysis of obtained viral sequences against the Edmonston strain MVNP gene and analysis of normal marrow samples.
Main Results:
- Full-length MVNP gene sequence successfully obtained from one patient's bone marrow.
- Over 700 base pairs of MVNP sequence identified in three additional Paget's disease patients.
- These MVNP sequences were absent in four healthy control marrow samples and exhibited multiple mutations compared to the standard Edmonston strain.
Conclusions:
- The findings provide molecular evidence consistent with a chronic measles virus infection in affected bone marrow sites of Paget's disease patients.
- The detected viral sequences, unique and present only in patients, strengthen the hypothesis of MV involvement in Paget's disease pathogenesis.
- Further research is warranted to elucidate the mechanism of chronic MV infection and its role in Paget's disease development.