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Mol Cell. 2017 Nov 16;68(4):645-658.e5. doi: 10.1016/j.molcel.2017.10.018.

NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis.

Author information

1
Center for Advanced Stem Cell and Regenerative Research, Graduate School of Dentistry, Tohoku University, Sendai 980-8575, Japan. Electronic address: hidefumi.fukushima.b7@tohoku.ac.jp.
2
Center for Advanced Stem Cell and Regenerative Research, Graduate School of Dentistry, Tohoku University, Sendai 980-8575, Japan; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
3
Center for Advanced Stem Cell and Regenerative Research, Graduate School of Dentistry, Tohoku University, Sendai 980-8575, Japan.
4
Center for Advanced Stem Cell and Regenerative Research, Graduate School of Dentistry, Tohoku University, Sendai 980-8575, Japan; Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Graduate School of Dentistry, Tohoku University, Sendai 980-8575, Japan.
5
Department of Medical Genetics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
6
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai 980-8574, Japan.
7
Corporate R&D, Asahi Kasei Corporation, 2-1 Samejima, Fuji-shi, Shizuoka 416-8501, Japan.
8
Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Graduate School of Dentistry, Tohoku University, Sendai 980-8575, Japan.
9
Department of Physiological Sciences and Molecular Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan.
10
Department of Dental Science, Graduate School of Dentistry, Kyushu University, Fukuoka 812-8582, Japan.
11
Institut Hospital del Mar d'Investigacions Mèdiques, CIBERONC, Dr Aiguader 88, 08003 Barcelona, Spain.
12
Division of Cell Regulation Systems, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
13
Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan.
14
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: wwei2@bidmc.harvard.edu.
15
Center for Advanced Stem Cell and Regenerative Research, Graduate School of Dentistry, Tohoku University, Sendai 980-8575, Japan. Electronic address: hinuzuka@tohoku.ac.jp.

Abstract

Hajdu-Cheney syndrome (HCS), a rare autosomal disorder caused by heterozygous mutations in NOTCH2, is clinically characterized by acro-osteolysis, severe osteoporosis, short stature, neurological symptoms, cardiovascular defects, and polycystic kidneys. Recent studies identified that aberrant NOTCH2 signaling and consequent osteoclast hyperactivity are closely associated with the bone-related disorder pathogenesis, but the exact molecular mechanisms remain unclear. Here, we demonstrate that sustained osteoclast activity is largely due to accumulation of NOTCH2 carrying a truncated C terminus that escapes FBW7-mediated ubiquitination and degradation. Mice with osteoclast-specific Fbw7 ablation revealed osteoporotic phenotypes reminiscent of HCS, due to elevated Notch2 signaling. Importantly, administration of Notch inhibitors in Fbw7 conditional knockout mice alleviated progressive bone resorption. These findings highlight the molecular basis of HCS pathogenesis and provide clinical insights into potential targeted therapeutic strategies for skeletal disorders associated with the aberrant FBW7/NOTCH2 pathway as observed in patients with HCS.

KEYWORDS:

FBW7; Hajdu-Cheney syndrome; NOTCH inhibitor; NOTCH2; SCF E3 ubiquitin ligase; osteoclast; osteoclastogenesis; osteolysis; osteoporosis; ubiquitination

PMID:
29149593
PMCID:
PMC5730348
[Available on 2018-11-16]
DOI:
10.1016/j.molcel.2017.10.018
[Indexed for MEDLINE]

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