NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis
Open accessAbstract
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.
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FBXW7 participates in osteoclastogenesis, and mice with osteoclast-specific Fbxw7 ablation (Fbxw7f/f Ctsk-Cre) exhibit an osteoporotic phenotype.
“FBXW7 has been reported to participate in osteoclastogenesis and mice with osteoclast-specific Fbxw7 ablation (Fbxw7f/f Ctsk-Cre) exhibit osteoporotic phenotype30.”
From Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis (2025) · cites this paper as [30]
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- Authors
- Fukushima, H., Shimizu, K., Watahiki, A., Hoshikawa, S., Kosho, T., Oba, D., Sakano, S., Arakaki, M., Yamada, A., Nagashima, K., Okabe, K., Fukumoto, S., Jimi, E., Bigas, A., Nakayama, K. I., Nakayama, K., Aoki, Y., Wei, W., & Inuzuka, H.
- Affiliations
- Tohoku University (JP)
- Beth Israel Deaconess Medical Center (US)
- Shinshu University (JP)
- Asahi Kasei (Japan) (JP)
- Fukuoka Dental College (JP)
- Kyushu University (JP)
- Hospital del Mar Research Institute (ES)
- Corresponding author
- Fukushima, Hidefumi
- Wei, Wenyi
- Inuzuka, Hiroyuki
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 68
- Issue
- 4
- Pages
- 645-658.e5
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC5730348
- OpenAlex
- W2770455327
- Cited by
- 46
- References
- 51
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 3 · 2020: 12 · 2019: 7 · 2018: 4
- FWCI
- 2.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- JSPS Kakenhi (17H04396, 26462829, 26253092, 16H05548, 16H05529, 16K15811)
- NIH (GM094777, CA177910)
- American Cancer Society
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Keywords
- Hajdu-Cheney syndrome, NOTCH2 mutation, FBXW7, proteasomal degradation, ubiquitination, bone resorption, osteoporosis, acro-osteolysis, Notch signaling, Notch inhibitors, bone disease
- MeSH terms
- F-Box-WD Repeat-Containing Protein 7, Animals, Cell Line, Mutation, Osteoporosis, Mice, Knockout, Hajdu-Cheney Syndrome, Receptor, Notch2, Ubiquitination, Proteolysis
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