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

作者：Fukushima Hidefumi^*; Shimizu Kouhei; Watahiki Asami; Hoshikawa Seira; Kosho Tomoki; Oba Daiju; Sakano Seiji; Arakaki Makiko; Yamada Aya; Nagashima Katsuyuki; Okabe Koji; Fukumoto Satoshi; Jimi Eijiro; Bigas Anna; Nakayama Keiichi I; Nakayama Keiko; Aoki Yoko; Wei Wenyi^*; Inuzuka Hiroyuki^*

来源：Molecular Cell, 2017, 68(4): 645-+.

DOI：10.1016/j.molcel.2017.10.018

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.

• 出版日期2017-11-16