title: Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption.
abstract: Notch receptors are determinants of cell fate and function and play a central role in skeletal development and bone remodeling. Hajdu Cheney syndrome, a disease characterized by osteoporosis and fractures, is associated with NOTCH2 mutations resulting in a truncated stable protein and gain-of-function. We created a mouse model reproducing the Hajdu Cheney syndrome by introducing a 6955C→T mutation in the Notch2 locus leading to a Q2319X change at the amino acid level. Notch2(Q2319X) heterozygous mutants were smaller and had shorter femurs than controls; and at 1 month of age they exhibited cancellous and cortical bone osteopenia. As the mice matured, cancellous bone volume was restored partially in male but not female mice, whereas cortical osteopenia persisted in both sexes. Cancellous bone histomorphometry revealed an increased number of osteoclasts and bone resorption, without a decrease in osteoblast number or bone formation. Osteoblast differentiation and function were not affected in Notch2(Q2319X) cells. The pre-osteoclast cell pool, osteoclast differentiation, and bone resorption in response to receptor activator of nuclear factor κB ligand in vitro were increased in Notch2(Q2319X) mutants. These effects were suppressed by the γ-secretase inhibitor LY450139. In conclusion, Notch2(Q2319X) mice exhibit cancellous and cortical bone osteopenia, enhanced osteoclastogenesis, and increased bone resorption.
authors.affiliation: From the Departments of Orthopaedic Surgery,; Medicine,. Electronic address: canalis@uchc.edu.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Canalis
authors.affiliation: From the Departments of Orthopaedic Surgery.
authors.forename: Lauren
authors.initials: L
authors.lastname: Schilling
authors.affiliation: Cell Biology, Genetics, and; Genome Sciences Biology.
authors.forename: Siu-Pok
authors.initials: SP
authors.lastname: Yee
authors.affiliation: Medicine,; Center on Aging, University of Connecticut Health Center, Farmington, Connecticut 06030.
authors.forename: Sun-Kyeong
authors.initials: SK
authors.lastname: Lee
authors.affiliation: From the Departments of Orthopaedic Surgery,; Medicine.
authors.forename: Stefano
authors.initials: S
authors.lastname: Zanotti
mesh_terms: D000818:Animals; D001851:Bone Diseases, Metabolic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D001862:Bone Resorption; D002454:Cell Differentiation; D004195:Disease Models, Animal; D005260:Female; D005269:Femur / Q000254:growth & development / Q000378:metabolism; D031845:Hajdu-Cheney Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis; D017354:Point Mutation; D051883:Receptor, Notch2 / Q000235:genetics* / Q000378:metabolism
chemical_list: C497765:Notch2 protein, mouse; D051883:Receptor, Notch2
keywords: Hajdu Cheney syndrome; Notch pathway; Notch protein; animal model; bone; osteoblast; osteoclast