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VCP Associated Inclusion Body Myopathy and Paget Disease of Bone Knock-In Mouse Model Exhibits Tissue Pathology Typical of Human Disease

Dominant mutations in the valosin containing protein (VCP) gene cause inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD). We have generated a knock-in mouse model with the common R155H mutation. Mice demonstrate progressive muscle weakness start...

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Autores principales: Badadani, Mallikarjun, Nalbandian, Angèle, Watts, Giles D., Vesa, Jouni, Kitazawa, Masashi, Su, Hailing, Tanaja, Jasmin, Dec, Eric, Wallace, Douglas C., Mukherjee, Jogeshwar, Caiozzo, Vincent, Warman, Matthew, Kimonis, Virginia E.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950155/
https://www.ncbi.nlm.nih.gov/pubmed/20957154
http://dx.doi.org/10.1371/journal.pone.0013183
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author Badadani, Mallikarjun
Nalbandian, Angèle
Watts, Giles D.
Vesa, Jouni
Kitazawa, Masashi
Su, Hailing
Tanaja, Jasmin
Dec, Eric
Wallace, Douglas C.
Mukherjee, Jogeshwar
Caiozzo, Vincent
Warman, Matthew
Kimonis, Virginia E.
author_facet Badadani, Mallikarjun
Nalbandian, Angèle
Watts, Giles D.
Vesa, Jouni
Kitazawa, Masashi
Su, Hailing
Tanaja, Jasmin
Dec, Eric
Wallace, Douglas C.
Mukherjee, Jogeshwar
Caiozzo, Vincent
Warman, Matthew
Kimonis, Virginia E.
author_sort Badadani, Mallikarjun
collection PubMed
description Dominant mutations in the valosin containing protein (VCP) gene cause inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD). We have generated a knock-in mouse model with the common R155H mutation. Mice demonstrate progressive muscle weakness starting approximately at the age of 6 months. Histology of mutant muscle showed progressive vacuolization of myofibrils and centrally located nuclei, and immunostaining shows progressive cytoplasmic accumulation of TDP-43 and ubiquitin-positive inclusion bodies in quadriceps myofibrils and brain. Increased LC3-II staining of muscle sections representing increased number of autophagosomes suggested impaired autophagy. Increased apoptosis was demonstrated by elevated caspase-3 activity and increased TUNEL-positive nuclei. X-ray microtomography (uCT) images show radiolucency of distal femurs and proximal tibiae in knock-in mice and uCT morphometrics shows decreased trabecular pattern and increased cortical wall thickness. Bone histology and bone marrow derived macrophage cultures in these mice revealed increased osteoclastogenesis observed by TRAP staining suggestive of Paget bone disease. The VCP(R155H/+) knock-in mice replicate the muscle, bone and brain pathology of inclusion body myopathy, thus representing a useful model for preclinical studies.
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spelling pubmed-29501552010-10-18 VCP Associated Inclusion Body Myopathy and Paget Disease of Bone Knock-In Mouse Model Exhibits Tissue Pathology Typical of Human Disease Badadani, Mallikarjun Nalbandian, Angèle Watts, Giles D. Vesa, Jouni Kitazawa, Masashi Su, Hailing Tanaja, Jasmin Dec, Eric Wallace, Douglas C. Mukherjee, Jogeshwar Caiozzo, Vincent Warman, Matthew Kimonis, Virginia E. PLoS One Research Article Dominant mutations in the valosin containing protein (VCP) gene cause inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD). We have generated a knock-in mouse model with the common R155H mutation. Mice demonstrate progressive muscle weakness starting approximately at the age of 6 months. Histology of mutant muscle showed progressive vacuolization of myofibrils and centrally located nuclei, and immunostaining shows progressive cytoplasmic accumulation of TDP-43 and ubiquitin-positive inclusion bodies in quadriceps myofibrils and brain. Increased LC3-II staining of muscle sections representing increased number of autophagosomes suggested impaired autophagy. Increased apoptosis was demonstrated by elevated caspase-3 activity and increased TUNEL-positive nuclei. X-ray microtomography (uCT) images show radiolucency of distal femurs and proximal tibiae in knock-in mice and uCT morphometrics shows decreased trabecular pattern and increased cortical wall thickness. Bone histology and bone marrow derived macrophage cultures in these mice revealed increased osteoclastogenesis observed by TRAP staining suggestive of Paget bone disease. The VCP(R155H/+) knock-in mice replicate the muscle, bone and brain pathology of inclusion body myopathy, thus representing a useful model for preclinical studies. Public Library of Science 2010-10-05 /pmc/articles/PMC2950155/ /pubmed/20957154 http://dx.doi.org/10.1371/journal.pone.0013183 Text en Badadani et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Badadani, Mallikarjun
Nalbandian, Angèle
Watts, Giles D.
Vesa, Jouni
Kitazawa, Masashi
Su, Hailing
Tanaja, Jasmin
Dec, Eric
Wallace, Douglas C.
Mukherjee, Jogeshwar
Caiozzo, Vincent
Warman, Matthew
Kimonis, Virginia E.
VCP Associated Inclusion Body Myopathy and Paget Disease of Bone Knock-In Mouse Model Exhibits Tissue Pathology Typical of Human Disease
title VCP Associated Inclusion Body Myopathy and Paget Disease of Bone Knock-In Mouse Model Exhibits Tissue Pathology Typical of Human Disease
title_full VCP Associated Inclusion Body Myopathy and Paget Disease of Bone Knock-In Mouse Model Exhibits Tissue Pathology Typical of Human Disease
title_fullStr VCP Associated Inclusion Body Myopathy and Paget Disease of Bone Knock-In Mouse Model Exhibits Tissue Pathology Typical of Human Disease
title_full_unstemmed VCP Associated Inclusion Body Myopathy and Paget Disease of Bone Knock-In Mouse Model Exhibits Tissue Pathology Typical of Human Disease
title_short VCP Associated Inclusion Body Myopathy and Paget Disease of Bone Knock-In Mouse Model Exhibits Tissue Pathology Typical of Human Disease
title_sort vcp associated inclusion body myopathy and paget disease of bone knock-in mouse model exhibits tissue pathology typical of human disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950155/
https://www.ncbi.nlm.nih.gov/pubmed/20957154
http://dx.doi.org/10.1371/journal.pone.0013183
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