High bone turnover in mice carrying a pathogenic Notch2-mutation causing Hajdu-Cheney syndrome
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High bone turnover in mice carrying a pathogenic Notch2-mutation causing Hajdu-Cheney syndrome. / Vollersen, Nele; Hermans-Borgmeyer, Irm; Cornils, Kerstin; Fehse, Boris; Rolvien, Tim; Triviai, Ioanna; Jeschke, Anke; Oheim, Ralf; Amling, Michael; Schinke, Thorsten; Yorgan, Timur Alexander.
In: J BONE MINER RES, Vol. 33, No. 1, 01.2018, p. 70-83.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - High bone turnover in mice carrying a pathogenic Notch2-mutation causing Hajdu-Cheney syndrome
AU - Vollersen, Nele
AU - Hermans-Borgmeyer, Irm
AU - Cornils, Kerstin
AU - Fehse, Boris
AU - Rolvien, Tim
AU - Triviai, Ioanna
AU - Jeschke, Anke
AU - Oheim, Ralf
AU - Amling, Michael
AU - Schinke, Thorsten
AU - Yorgan, Timur Alexander
N1 - This article is protected by copyright. All rights reserved.
PY - 2018/1
Y1 - 2018/1
N2 - Hajdu-Cheney syndrome (HCS) is a rare autosomal-dominant disorder primarily characterized by acro-osteolysis and early-onset osteoporosis. Genetically, HCS is caused by nonsense or deletion mutations within exon 34 of the NOTCH2 gene, resulting in premature translational termination and production of C-terminally truncated NOTCH2 proteins that are predicted to activate NOTCH2-dependent signaling. To understand the role of Notch2 in bone remodeling, we developed a mouse model of HCS by introducing a pathogenic mutation (6272delT) into the murine Notch2 gene. By μCT and undecalcified histology, we observed generalized osteopenia in two independent mouse lines derived by injection of different targeted embryonic stem (ES) cell clones, yet acro-osteolysis did not occur until the age of 52 weeks. Cellular and dynamic histomorphometry revealed a high bone turnover situation in Notch2+/HCS mice, since osteoblast and osteoclast indices were significantly increased compared with wild-type littermates. Whereas ex vivo cultures failed to uncover cell-autonomous gain-of-functions within the osteoclast or osteoblast lineage, an unbiased RNA sequencing approach identified Tnfsf11 and Il6 as Notch-signaling target genes in bone marrow cells cultured under osteogenic conditions. Because we further observed that the high-turnover pathology of Notch2+/HCS mice was fully normalized by alendronate treatment, our results demonstrate that mutational activation of Notch2 does not directly control osteoblast activity but favors a pro-osteoclastic gene expression pattern, which in turn triggers high bone turnover. © 2017 American Society for Bone and Mineral Research.
AB - Hajdu-Cheney syndrome (HCS) is a rare autosomal-dominant disorder primarily characterized by acro-osteolysis and early-onset osteoporosis. Genetically, HCS is caused by nonsense or deletion mutations within exon 34 of the NOTCH2 gene, resulting in premature translational termination and production of C-terminally truncated NOTCH2 proteins that are predicted to activate NOTCH2-dependent signaling. To understand the role of Notch2 in bone remodeling, we developed a mouse model of HCS by introducing a pathogenic mutation (6272delT) into the murine Notch2 gene. By μCT and undecalcified histology, we observed generalized osteopenia in two independent mouse lines derived by injection of different targeted embryonic stem (ES) cell clones, yet acro-osteolysis did not occur until the age of 52 weeks. Cellular and dynamic histomorphometry revealed a high bone turnover situation in Notch2+/HCS mice, since osteoblast and osteoclast indices were significantly increased compared with wild-type littermates. Whereas ex vivo cultures failed to uncover cell-autonomous gain-of-functions within the osteoclast or osteoblast lineage, an unbiased RNA sequencing approach identified Tnfsf11 and Il6 as Notch-signaling target genes in bone marrow cells cultured under osteogenic conditions. Because we further observed that the high-turnover pathology of Notch2+/HCS mice was fully normalized by alendronate treatment, our results demonstrate that mutational activation of Notch2 does not directly control osteoblast activity but favors a pro-osteoclastic gene expression pattern, which in turn triggers high bone turnover. © 2017 American Society for Bone and Mineral Research.
KW - Journal Article
U2 - 10.1002/jbmr.3283
DO - 10.1002/jbmr.3283
M3 - SCORING: Journal article
C2 - 28856714
VL - 33
SP - 70
EP - 83
JO - J BONE MINER RES
JF - J BONE MINER RES
SN - 0884-0431
IS - 1
ER -