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    Contributions of the measles virus nucleocapsid gene and the SQSTM1/p62(P392L) mutation to Paget's disease

    Cell Metab. 2011 Jan 5;13(1):23-34.

    In this paper marrow cells from 12 Paget’s disease patients harboring p62(P392L) mutations in the sequestosome 1/p62gene and eight normals were tested for measles virus nucleocapsid protein (MVNP) expression and pagetic OCL formation. The authors found that eight out of twelve patients expressed the MVNP gene and formed pagetic OCL in vitro, which were inhibited by antisense-MVNP. In contrast, four out of twelve patients lacked MVNP and formed normal OCL that were hyperresponsive to RANKL but unaffected by antisense-MVNP. In addition they found that mice coexpressing MVNP and p62P394L developed dramatic Paget's-like bone lesions. These results imply that mutations in both p62 and MVNP are involved in the development of Paget’s disease in some patients.
    Authors: Kurihara N, Hiruma Y, Yamana K, et. al

    Paget's disease (PD) is characterized by abnormal osteoclasts (OCL) that secrete high IL-6 levels and induce exuberant bone formation. Because measles virus nucleocapsid gene (MVNP) and the p62(P392L) mutation are implicated in PD, marrows from 12 PD patients harboring p62(P392L) and eight normals were tested for MVNP expression and pagetic OCL formation. Eight out of twelve patients expressed MVNP and formed pagetic OCL in vitro, which were inhibited by antisense-MVNP. Four out of twelve patients lacked MVNP and formed normal OCL that were hyperresponsive to RANKL but unaffected by antisense-MVNP. Similarly, mice expressing only p62(P394L) formed normal OCL, while mice expressing MVNP in OCL, with or without p62(P394L), developed pagetic OCL and expressed high IL-6 levels dependent on p38MAPK activation. IL-6 deficiency in MVNP mice abrogated pagetic OCL development in vitro. Mice coexpressing MVNP and p62(P394L) developed dramatic Paget's-like bone lesions. These results suggest that p62(P394L) and IL-6 induction by MVNP play key roles in PD.

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