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

Abstract

Summary Hajdu-Cheney syndrome (HCS), a rare autosomal disorder caused by heterozygous mutations in NOTCH2, is clinically characterized by acroosteolysis, 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.

Ubiquitylomes Analysis of the Whole blood in Postmenopausal Osteoporosis Patients and healthy Postmenopausal Women

“…E) were reported all related to bone metabolism. These results reflect those of Fukushima (2017), who found that sustained osteoclast activity is largely due to accumulation of NOTCH2 carrying a truncated C terminus that escapes FBW7‐mediated ubiquitination and degradation. Salivary secretion may contribute to postmenopausal bone health.…”

The Hajdu Cheney mutation sensitizes mice to the osteolytic actions of tumor necrosis factor α

“…The PEST domain is recognized by the E3 ligase complex for ubiquitin-mediated degradation of NOTCH2. Therefore, the mutations result in the translation of a truncated NOTCH2 protein resistant to ubiquitin-dependent degradation and a gain-of-NOTCH2 function (23). To investigate the mechanisms responsible for HCS, we created a mouse model termed Notch2 tm1.1Ecan harboring a point mutation (6955C3 T) in exon 34 of Notch2 upstream of the PEST domain.…”

Mouse Cre Models for the Study of Bone Diseases

“…There have been no reports showing a skeletal phenotype in hetero- or homozygous LysM-Cre KI mice in the absence of a floxed target gene. The CtsK-Cre KI and LysM-Cre KI lines were used for the etiological study of rare bone disorders such as Hajdu-Cheney syndrome and cherubism [60, 64]. These studies have shown that accumulation of NOTCH2 protein in osteoclasts and increased activation of SYK by accumulation of SH3BP2 protein in myeloid lineage cells are responsible for the bone phenotypes, respectively.…”