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 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.
Department of Pediatrics, University of California Irvine, Irvine, California, United States of America.
Mallikarjun
M
Badadani
Angèle
A
Nalbandian
Giles D
GD
Watts
Jouni
J
Vesa
Masashi
M
Kitazawa
Hailing
H
Su
Jasmin
J
Tanaja
Eric
E
Dec
Douglas C
DC
Wallace
Jogeshwar
J
Mukherjee
Vincent
V
Caiozzo
Matthew
M
Warman
Virginia E
VE
Kimonis
D000251:Adenosine Triphosphatases / Q000502:physiology*; D000818:Animals; D018797:Cell Cycle Proteins / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D018979:Myositis, Inclusion Body / Q000503:physiopathology*; D010001:Osteitis Deformans / Q000473:pathology*; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse