A Negative Search for a Paramyxoviral Etiology of Paget's Disease of Bone: Molecular, Immunological, and Ultrastructural Studies in U.K. Patients

Abstract

Paget's disease of bone is a common bone disease characterized by increased and disorganized bone remodeling at focal sites throughout the skeleton. The etiology of the disease is unresolved. A persistent viral infection has long been suggested to cause the disease. Antigen and/or nucleic acid sequences of paramyxoviruses (in particular measles virus [MV], canine distemper virus [CDV], and respiratory syncytial virus [RSV]) have been reported in pagetic bone by a number of groups; however, others have been unable to confirm this and so far no virus has been isolated from patients. Here, we reexamined the question of viral involvement in Paget's disease in a study involving 53 patients with established disease recruited from seven centers throughout the United Kingdom. Thirty-seven patients showed clear signs of active disease by bone scan and/or histological assessment of the bone biopsy specimens and 12 of these had not received any therapy before samples were taken. Presence of paramyxovirus nucleic acid sequences was sought in bone biopsy specimens, bone marrow, or peripheral blood mononuclear cells using reverse-transcription polymerase chain reaction (RT-PCR) with a total of 18 primer sets (7 of which were nested), including 10 primer sets (including 3 nested sets) specifically for MV or CDV. For each patient at least one sample was tested with all primer sets by RT-PCR and no evidence for the presence of paramyxovirus RNA was found in any patient. In 6 patients, bone biopsy specimens with clear histological evidence of active disease tested negative for presence of measles and CDV using immunocytochemistry (ICC) and in situ hybridization (ISH). Intranuclear inclusion bodies, similar to those described by others previously, were seen in pagetic osteoclasts. The pagetic inclusions were straight, smooth tubular structures packed tightly in parallel bundles and differed from nuclear inclusions, known to represent MV nucleocapsids, in a patient with subacute sclerosing panencephalitis (SSPE) in which undulating, diffuse structures were found, arranged loosely in a nonparallel fashion. In the absence of amplification of viral sequences from tissues that contain frequent nuclear inclusions and given that identical inclusions are found in other bone diseases with a proven genetic, rather than environmental, etiology, it is doubtful whether the inclusions in pagetic osteoclasts indeed represent viral nucleocapsids. Our findings in this large group of patients recruited from throughout the United Kingdom do not support a role for paramyxovirus in the etiology of Paget's disease. (J Bone Miner Res 2000;15:2315-2329)

Morbilliviruses and human disease

“…No wild-type sequences were obtained, which argues against vaccination being responsible for a delay in OS presentation [151]. In PD, some nucleotides differed from the published vaccine strain, although when five of these were examined more closely [152], they were due to errors in the sequence used for comparison. Others have not been able to identify MV RNA in samples from patients with PD [152][153][154].…”

“…In PD, some nucleotides differed from the published vaccine strain, although when five of these were examined more closely [152], they were due to errors in the sequence used for comparison. Others have not been able to identify MV RNA in samples from patients with PD [152][153][154]. The situation in OS is equally unresolved, as some have provided evidence that MV RNA is present in bone samples [140,143,155] and others have not been able to confirm these data [156].…”

“…The significance of these results is not clear and contamination cannot be ruled out. Several other studies have not been able to confirm the presence of CDVspecific RNA in nucleic acids extracted from bone, but of course in science it is formally impossible to prove the absence of anything [152,154]. ISH studies using CDV-specific probes were carried out [171].…”

Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone

“…The hypothezised paramyxovirus origin of these inclusions is still debated. (14)(15)(16)(17)(18)(19)(20)(21)(22) Epidemiologic studies have indicated a role for genetic factors in at least a subset of the cases. (23)(24)(25)(26)(27)(28) Some families were reported with a clear autosomal mode of inheritance.…”

Pagetic Bone Lesions in a Patient with Early Breast Cancer

“…PDB is characterized by a localized increase in osteoclast activity leading to excessive focal resorption of bone, followed by the replacement of normal marrow by vascular and brous connective tissue, and disorganized formation of new bone (1,5). Although the cause of PDB is unknown (1,5), several studies strongly suggest the involvement of a genetic component (6,7), and a role for paramyxoviruses has been suggested ( (8), but see (9)) in the etiology of this disorder. Upregulation of interleukin 6 secretion and receptor expression by pagetic bone and marrow cells together with their hypersensitivity to the effects of 1,25 dihydroxyvitamin D 3 , and the role of the receptors for the activation of NFkB (RANK) in the regulation of osteoclast formation could explain the pathological activity of osteoclasts (1,8).…”