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:	Mallikarjun Badadani, Angèle Nalbandian, Giles D Watts, Jouni Vesa, Masashi Kitazawa, Hailing Su, Jasmin Tanaja, Eric Dec, Douglas C Wallace, Jogeshwar Mukherjee, Vincent Caiozzo, Matthew Warman, Virginia E Kimonis
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2cdd0745e5b14c47b170f59034a2bb34
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spelling	oai:doaj.org-article:2cdd0745e5b14c47b170f59034a2bb342021-11-18T07:03:40ZVCP associated inclusion body myopathy and paget disease of bone knock-in mouse model exhibits tissue pathology typical of human disease.1932-620310.1371/journal.pone.0013183https://doaj.org/article/2cdd0745e5b14c47b170f59034a2bb342010-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20957154/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Dominant 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.Mallikarjun BadadaniAngèle NalbandianGiles D WattsJouni VesaMasashi KitazawaHailing SuJasmin TanajaEric DecDouglas C WallaceJogeshwar MukherjeeVincent CaiozzoMatthew WarmanVirginia E KimonisPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 10 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mallikarjun Badadani Angèle Nalbandian Giles D Watts Jouni Vesa Masashi Kitazawa Hailing Su Jasmin Tanaja Eric Dec Douglas C Wallace Jogeshwar Mukherjee Vincent Caiozzo Matthew Warman Virginia E Kimonis VCP associated inclusion body myopathy and paget disease of bone knock-in mouse model exhibits tissue pathology typical of human disease.
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	article
author	Mallikarjun Badadani Angèle Nalbandian Giles D Watts Jouni Vesa Masashi Kitazawa Hailing Su Jasmin Tanaja Eric Dec Douglas C Wallace Jogeshwar Mukherjee Vincent Caiozzo Matthew Warman Virginia E Kimonis
author_facet	Mallikarjun Badadani Angèle Nalbandian Giles D Watts Jouni Vesa Masashi Kitazawa Hailing Su Jasmin Tanaja Eric Dec Douglas C Wallace Jogeshwar Mukherjee Vincent Caiozzo Matthew Warman Virginia E Kimonis
author_sort	Mallikarjun Badadani
title	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_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_sort	vcp associated inclusion body myopathy and paget disease of bone knock-in mouse model exhibits tissue pathology typical of human disease.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/2cdd0745e5b14c47b170f59034a2bb34
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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.

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