TY - JOUR
T1 - Genetic Disruption of Anoctamin 5 in Mice Replicates Human Gnathodiaphyseal Dysplasia (GDD)
AU - Wang, Xiaoyu
AU - Liu, Xiu
AU - Dong, Rui
AU - Liang, Chao
AU - Reichenberger, Ernst J.
AU - Hu, Ying
N1 - Funding Information:
Acknowledgements This work was supported by the National Natural Science Foundation of China (Grant # 81570958); Beijing Natural Science Foundation (Grant #7162075); High-level Talents of Beijing Health System (Grant #2013-3-036); and Scientific Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (Grant # 2015-1098).
PY - 2019/6/15
Y1 - 2019/6/15
N2 - Gnathodiaphyseal dysplasia (GDD; OMIM#166260) is a rare skeletal disorder which is mainly characterized by cemento-osseous lesions in mandibles, bone fragility, bowing and diaphyseal sclerosis of tubular bones. GDD is caused by point mutations in Anoctamin-5 (ANO5); however, the disease mechanisms remain unclear. Here we generated Ano5-knockout (KO) mice using a CRISPR/Cas 9 approach to study loss of function aspects of GDD mutations. Homozygous Ano5 knockout mice (Ano5−/−) replicate some typical traits of human GDD including massive jawbones, bowing tibia, sclerosis and cortical thickening of femoral and tibial diaphyses. Serum alkaline phosphatase (ALP) levels were elevated in Ano5−/− mice as in GDD patients. Calvaria-derived Ano5−/− osteoblast cultures show increased osteoblastogenesis, which is consistent with our previous in vitro observations. Bone matrix is hypermineralized, and the expression of bone formation-related factors is enhanced in Ano5−/− mice, suggesting that the osteogenic anomaly arises from a genetic disruption of Ano5. We believe this new mouse model will shed more light on the development of skeletal abnormalities in GDD on a cellular and molecular level.
AB - Gnathodiaphyseal dysplasia (GDD; OMIM#166260) is a rare skeletal disorder which is mainly characterized by cemento-osseous lesions in mandibles, bone fragility, bowing and diaphyseal sclerosis of tubular bones. GDD is caused by point mutations in Anoctamin-5 (ANO5); however, the disease mechanisms remain unclear. Here we generated Ano5-knockout (KO) mice using a CRISPR/Cas 9 approach to study loss of function aspects of GDD mutations. Homozygous Ano5 knockout mice (Ano5−/−) replicate some typical traits of human GDD including massive jawbones, bowing tibia, sclerosis and cortical thickening of femoral and tibial diaphyses. Serum alkaline phosphatase (ALP) levels were elevated in Ano5−/− mice as in GDD patients. Calvaria-derived Ano5−/− osteoblast cultures show increased osteoblastogenesis, which is consistent with our previous in vitro observations. Bone matrix is hypermineralized, and the expression of bone formation-related factors is enhanced in Ano5−/− mice, suggesting that the osteogenic anomaly arises from a genetic disruption of Ano5. We believe this new mouse model will shed more light on the development of skeletal abnormalities in GDD on a cellular and molecular level.
KW - Ano5
KW - Genetic disorder
KW - Gnathodiaphyseal dysplasia
KW - Osteoblastogenesis
KW - Skeletal phenotype
UR - http://www.scopus.com/inward/record.url?scp=85061048306&partnerID=8YFLogxK
U2 - 10.1007/s00223-019-00528-x
DO - 10.1007/s00223-019-00528-x
M3 - Journal article
C2 - 30712070
AN - SCOPUS:85061048306
SN - 0171-967X
VL - 104
SP - 679
EP - 689
JO - Calcified Tissue International
JF - Calcified Tissue International
IS - 6
ER -
