Elsevier

Bone

Volume 24, Issue 5, Supplement 1, May 1999, Pages 19S-21S
Bone

Slow Virus Infections and Paget’s Disease
Paramyxoviruses and Paget’s disease: the affirmative view

https://doi.org/10.1016/S8756-3282(99)00033-2Get rights and content

Introduction

Despite the major advances that have been made since the founding of the NARPD 25 years ago, particularly in terms of treatment of the disorder, one major question has yet to be answered: What causes Paget’s disease? This question has perplexed many investigators since Sir James Paget first accurately described the disorder over 120 years ago. Paget thought that the disorder was inflammatory in origin, hence his term osteitis deformans. However, over the past 20 years, workers have concentrated on a potential viral etiology. To ascertain whether paramyxoviruses are involved in Paget’s disease, I feel it is necessary to answer four major questions:

  • 1.

    Are paramyxoviruses present in pagetic bone?

  • 2.

    Is there evidence to suggest how they got there, and any predilection of the viruses for bone?

  • 3.

    How do the viruses cause the disease?

  • 4.

    What else do we know about the disease that can be explained by a viral etiology?

Section snippets

Detection of paramyxoviruses in pagetic bone

Since the early 1970s, various techniques have been used to demonstrate paramyxoviruses in pagetic bone. The first clues came from electron microscopy (EM), which showed viral-like inclusion bodies in pagetic osteoclasts.18 It has recently been suggested that these inclusions do not resemble those found in, for example, chronic neurological infections with measles virus (MV) and are, therefore, not derived from paramyxoviruses. However, a variety of inclusions with differing morphology can be

Viral route of entry and predilection sites

Paramyxoviruses are known to be spread by aerosol transmission following close contact with an infected individual. Distemper-infected dogs, for example, following infection, shed virus in all secretions and excretions, whether they show clinical signs or not; that is, dogs can be infected and shed virus prior to mounting a successful immune response and not develop the characteristic disease.

Following local infection in the respiratory tract, the virus spreads to the lymphopoietic tissues and

Effects of viral infection in Paget’s disease

Previously, raised levels of serum interleukin-6 (IL-6) have been detected in pagetic patients. We have shown upregulation of IL-6 and its receptor in pagetic osteoclasts and, similarly, raised levels of the protooncogene c-fos.6, 7 IL-6 is known to be involved in osteoclast precursor recruitment, and c-fos has been shown in transgenic studies to be involved in increasing osteoclastic activity. It has been shown that the process of programmed cell death, or apoptosis, is a potent regulator of

Further clues toward a viral etiology

Two of the most striking features of Paget’s disease are the high familial prevalence of the disorder, and its focal nature. Recent genetic linkage analysis studies have simultaneously revealed a locus for the disorder on chromosome 18q.4, 12 Within this locus is the Bcl-2 gene. Some defect in the gene itself, or its regulatory elements, could explain the genetic predisposition to Paget’s disease.

Unfortunately, it is not possible to explain Paget’s disease purely by genetics. There is a

Summary

Evidence has accumulated over the past 20 years to implicate paramyxoviruses in the etiopathology of Paget’s disease. In the USA, the predominant virus detected is MV, whereas in northwestern England, CDV is most prevalent. The viruses are known to be easily spread by aerosol transmission to the respiratory tissues, from which they gain entry to the skeletal tissues via the hematopoietic system. Another characteristic of these viruses is their ability to persist at very low levels, thus evading

Acknowledgements

The author expresses extreme gratitude to the NARPD, initially for funding doctoral work, and then for their continuing support over recent years. I also thank the Wellcome Trust for the support of a veterinary fellowship and the Paget Foundation USA for their support. I also thank and acknowledge several members of the Bone Disease Research Centre, both past and present, including Professors David Anderson, Paul Sharpe, Barbara Mawer, Tony Freemont, Dr. Margaret Gordon, Dr. David Webber, Dr.

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