Cargando…
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...
Autores principales: | , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1782187632686530560 |
---|---|
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. |
format | Text |
id | pubmed-2950155 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT badadanimallikarjun vcpassociatedinclusionbodymyopathyandpagetdiseaseofboneknockinmousemodelexhibitstissuepathologytypicalofhumandisease AT nalbandianangele vcpassociatedinclusionbodymyopathyandpagetdiseaseofboneknockinmousemodelexhibitstissuepathologytypicalofhumandisease AT wattsgilesd vcpassociatedinclusionbodymyopathyandpagetdiseaseofboneknockinmousemodelexhibitstissuepathologytypicalofhumandisease AT vesajouni vcpassociatedinclusionbodymyopathyandpagetdiseaseofboneknockinmousemodelexhibitstissuepathologytypicalofhumandisease AT kitazawamasashi vcpassociatedinclusionbodymyopathyandpagetdiseaseofboneknockinmousemodelexhibitstissuepathologytypicalofhumandisease AT suhailing vcpassociatedinclusionbodymyopathyandpagetdiseaseofboneknockinmousemodelexhibitstissuepathologytypicalofhumandisease AT tanajajasmin vcpassociatedinclusionbodymyopathyandpagetdiseaseofboneknockinmousemodelexhibitstissuepathologytypicalofhumandisease AT deceric vcpassociatedinclusionbodymyopathyandpagetdiseaseofboneknockinmousemodelexhibitstissuepathologytypicalofhumandisease AT wallacedouglasc vcpassociatedinclusionbodymyopathyandpagetdiseaseofboneknockinmousemodelexhibitstissuepathologytypicalofhumandisease AT mukherjeejogeshwar vcpassociatedinclusionbodymyopathyandpagetdiseaseofboneknockinmousemodelexhibitstissuepathologytypicalofhumandisease AT caiozzovincent vcpassociatedinclusionbodymyopathyandpagetdiseaseofboneknockinmousemodelexhibitstissuepathologytypicalofhumandisease AT warmanmatthew vcpassociatedinclusionbodymyopathyandpagetdiseaseofboneknockinmousemodelexhibitstissuepathologytypicalofhumandisease AT kimonisvirginiae vcpassociatedinclusionbodymyopathyandpagetdiseaseofboneknockinmousemodelexhibitstissuepathologytypicalofhumandisease |