Brya Matthews; Tim Cundy

Disclosures

Expert Rev Endocrinol Metab. 2009;4(6):651-668. 

In This Article

Paramyxoviruses & Paget's Disease

The observation that paramyxoviral-like nuclear inclusions are commonly present in pagetic osteoclasts sparked much debate regarding a role for viruses in the etiology of the disease.[105,106] A number of publications report detection of mRNA or protein from measles virus,[71,107–109] canine distemper virus[110] or respiratory syncytial virus,[111] in samples from patients with Paget's disease, but generally not in controls. However, other groups have repeatedly failed to detect viral RNA or antigens,[112–115] and live paramyxoviruses have never been isolated from pagetic tissue.

Further evidence for a potential role for viruses in the disease etiology stems from the observation that infection with paramyxoviruses can induce Paget-like changes in osteoclasts. Human bone marrow cells expressing measles nucleocapsid protein produce increased numbers of large, highly nucleated osteoclasts, and IL-6 levels are increased.[116] Infection of mouse bone marrow with measles virus produces similar results,[117] while infection of human osteoclast precursors with canine distemper virus stimulates expression of NF-κB and SQSTM1, increases osteoclast formation and resorption, and increases the size and number of nuclei in the cells.[118] Mice expressing the measles nucleocapsid gene under the control of the Trap promoter develop high bone turnover lesions in their vertebrae that worsen with age.[119] Whether lesions were also present in the limbs was not reported. In addition, bone marrow cultured from mutant mice was hyper-responsive to 1,25(OH)2D3 and produced high IL-6 levels. Although these data suggest that paramyxoviral infection may reproduce some aspects of the cellular phenotype of Paget's disease, there is no evidence that this response is specific for a particular virus, and it might be mediated by virus-induced increases in cytokines. Large, highly nucleated osteoclasts have also been identified in nonpagetic bone treated with bisphosphonate, again suggesting that this morphology could be a nonspecific response.[120]

While nuclear and cytoplasmic inclusions are a feature of pagetic osteoclasts, they are not specific to this disease. Similar inclusions have also been found in osteoclasts or macrophages in other conditions, not attributed to viral infection, including osteopetrosis.[121] Thus, they might represent a nonspecific stress response in osteoclasts. Nuclear inclusions are also seen in brain cells from patients with subacute sclerosis panencephalitis, a fatal condition caused by a long-term measles virus infection of the brain.[122] While these inclusions are similar in size to those in Paget's disease, their organization appears different.[112] Recent work has suggested that the inclusion bodies contain SQSTM1, VCP and ubiquitin,[123] suggesting that, rather than being viral particles, they may be protein aggregates formed owing to defects in the cellular degradation machinery, which are probably exacerbated by aging. In the past, measles virus has also been implicated in other conditions, such as inflammatory bowel disease, multiple sclerosis and autism.[124–126] These links are not currently thought to be etiologically important.[127–129] Such studies of disease association are complicated by the fact that there can be persistence of measles virus RNA in human tissue long after an acute infection, without evidence of ill-effects.[126]

The decline in prevalence and severity of Paget's disease in various countries seems to have antedated the introduction in Western countries of vaccination both of dogs for distemper (~1955) and children for measles (~1970). Therefore, the hypothesis that paramyxoviruses are the environmental factor involved in triggering Paget's disease needs further proof.

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