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Osteoblast-specific Notch2 inactivation causes increased trabecular bone mass at specific sites of the appendicular skeleton

Standard

Osteoblast-specific Notch2 inactivation causes increased trabecular bone mass at specific sites of the appendicular skeleton. / Yorgan, Timur; Vollersen, Nele; Riedel, Christoph; Jeschke, Anke; Peters, Stephanie; Busse, Bjoern; Amling, Michael; Schinke, Thorsten.

In: BONE, Vol. 87, 06.2016, p. 136-46.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Yorgan, T, Vollersen, N, Riedel, C, Jeschke, A, Peters, S, Busse, B, Amling, M & Schinke, T 2016, 'Osteoblast-specific Notch2 inactivation causes increased trabecular bone mass at specific sites of the appendicular skeleton', BONE, vol. 87, pp. 136-46. https://doi.org/10.1016/j.bone.2016.04.012

APA

Yorgan, T., Vollersen, N., Riedel, C., Jeschke, A., Peters, S., Busse, B., Amling, M., & Schinke, T. (2016). Osteoblast-specific Notch2 inactivation causes increased trabecular bone mass at specific sites of the appendicular skeleton. BONE, 87, 136-46. https://doi.org/10.1016/j.bone.2016.04.012

Vancouver

Yorgan T, Vollersen N, Riedel C, Jeschke A, Peters S, Busse B et al. Osteoblast-specific Notch2 inactivation causes increased trabecular bone mass at specific sites of the appendicular skeleton. BONE. 2016 Jun;87:136-46. https://doi.org/10.1016/j.bone.2016.04.012

Bibtex

@article{e3bbb18baf2b4109bc70940f76e1e08e,
title = "Osteoblast-specific Notch2 inactivation causes increased trabecular bone mass at specific sites of the appendicular skeleton",
abstract = "Notch signaling is a key pathway controlling various cell fate decisions during embryogenesis and adult life. It is activated by binding of specific ligands to four different Notch receptors that are subsequently cleaved by presenilins to release an intracellular domain that enters the nucleus and activates specific transcription factors. While the skeletal analysis of various mouse models with activated or inactivated Notch signaling has demonstrated a general impact of this pathway on bone remodeling, the more recent identification of NOTCH2 mutations in individuals with Hajdu-Cheney syndrome (HCS) has highlighted its human relevance. Since HCS is primarily characterized by skeletal defects, these latter findings led us to analyze the specific role of Notch2 in skeletal remodeling. After observing Notch2 expression in osteoblasts and osteoclasts, we utilized Runx2-Cre and Lyz2-Cre mice to inactivate Notch2 in cells of the osteoblast or osteoclast lineage, respectively. Whereas Notch2(fl/fl)/Lyz2-Cre mice did not display significant alterations of skeletal growth, bone mass or remodeling, Notch2(fl/fl)/Runx2-Cre mice progressively developed skeletal abnormalities in long bones. More specifically, these mice displayed a striking increase of trabecular bone mass in the proximal femur and the distal tibia at 6 and 12months of age. Whereas undecalcified sectioning of the respective regions did not reveal impaired osteocyte differentiation as a potential trigger for the observed phenotype, ex vivo experiments with bone marrow cells identified an increased osteogenic capacity of Notch2(fl/fl)/Runx2-Cre cultures. Collectively, our findings demonstrate that Notch2 physiologically regulates bone remodeling by inhibiting trabecular bone formation in the appendicular skeleton. Understanding the underlying mechanisms may help to improve diagnosis and therapy of HCS.",
keywords = "Journal Article",
author = "Timur Yorgan and Nele Vollersen and Christoph Riedel and Anke Jeschke and Stephanie Peters and Bjoern Busse and Michael Amling and Thorsten Schinke",
note = "Copyright {\textcopyright} 2016 Elsevier Inc. All rights reserved.",
year = "2016",
month = jun,
doi = "10.1016/j.bone.2016.04.012",
language = "English",
volume = "87",
pages = "136--46",
journal = "BONE",
issn = "8756-3282",
publisher = "Elsevier Inc.",

}

RIS

TY - JOUR

T1 - Osteoblast-specific Notch2 inactivation causes increased trabecular bone mass at specific sites of the appendicular skeleton

AU - Yorgan, Timur

AU - Vollersen, Nele

AU - Riedel, Christoph

AU - Jeschke, Anke

AU - Peters, Stephanie

AU - Busse, Bjoern

AU - Amling, Michael

AU - Schinke, Thorsten

N1 - Copyright © 2016 Elsevier Inc. All rights reserved.

PY - 2016/6

Y1 - 2016/6

N2 - Notch signaling is a key pathway controlling various cell fate decisions during embryogenesis and adult life. It is activated by binding of specific ligands to four different Notch receptors that are subsequently cleaved by presenilins to release an intracellular domain that enters the nucleus and activates specific transcription factors. While the skeletal analysis of various mouse models with activated or inactivated Notch signaling has demonstrated a general impact of this pathway on bone remodeling, the more recent identification of NOTCH2 mutations in individuals with Hajdu-Cheney syndrome (HCS) has highlighted its human relevance. Since HCS is primarily characterized by skeletal defects, these latter findings led us to analyze the specific role of Notch2 in skeletal remodeling. After observing Notch2 expression in osteoblasts and osteoclasts, we utilized Runx2-Cre and Lyz2-Cre mice to inactivate Notch2 in cells of the osteoblast or osteoclast lineage, respectively. Whereas Notch2(fl/fl)/Lyz2-Cre mice did not display significant alterations of skeletal growth, bone mass or remodeling, Notch2(fl/fl)/Runx2-Cre mice progressively developed skeletal abnormalities in long bones. More specifically, these mice displayed a striking increase of trabecular bone mass in the proximal femur and the distal tibia at 6 and 12months of age. Whereas undecalcified sectioning of the respective regions did not reveal impaired osteocyte differentiation as a potential trigger for the observed phenotype, ex vivo experiments with bone marrow cells identified an increased osteogenic capacity of Notch2(fl/fl)/Runx2-Cre cultures. Collectively, our findings demonstrate that Notch2 physiologically regulates bone remodeling by inhibiting trabecular bone formation in the appendicular skeleton. Understanding the underlying mechanisms may help to improve diagnosis and therapy of HCS.

AB - Notch signaling is a key pathway controlling various cell fate decisions during embryogenesis and adult life. It is activated by binding of specific ligands to four different Notch receptors that are subsequently cleaved by presenilins to release an intracellular domain that enters the nucleus and activates specific transcription factors. While the skeletal analysis of various mouse models with activated or inactivated Notch signaling has demonstrated a general impact of this pathway on bone remodeling, the more recent identification of NOTCH2 mutations in individuals with Hajdu-Cheney syndrome (HCS) has highlighted its human relevance. Since HCS is primarily characterized by skeletal defects, these latter findings led us to analyze the specific role of Notch2 in skeletal remodeling. After observing Notch2 expression in osteoblasts and osteoclasts, we utilized Runx2-Cre and Lyz2-Cre mice to inactivate Notch2 in cells of the osteoblast or osteoclast lineage, respectively. Whereas Notch2(fl/fl)/Lyz2-Cre mice did not display significant alterations of skeletal growth, bone mass or remodeling, Notch2(fl/fl)/Runx2-Cre mice progressively developed skeletal abnormalities in long bones. More specifically, these mice displayed a striking increase of trabecular bone mass in the proximal femur and the distal tibia at 6 and 12months of age. Whereas undecalcified sectioning of the respective regions did not reveal impaired osteocyte differentiation as a potential trigger for the observed phenotype, ex vivo experiments with bone marrow cells identified an increased osteogenic capacity of Notch2(fl/fl)/Runx2-Cre cultures. Collectively, our findings demonstrate that Notch2 physiologically regulates bone remodeling by inhibiting trabecular bone formation in the appendicular skeleton. Understanding the underlying mechanisms may help to improve diagnosis and therapy of HCS.

KW - Journal Article

U2 - 10.1016/j.bone.2016.04.012

DO - 10.1016/j.bone.2016.04.012

M3 - SCORING: Journal article

C2 - 27102824

VL - 87

SP - 136

EP - 146

JO - BONE

JF - BONE

SN - 8756-3282

ER -