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.

Hajdu-Cheney综合征（HCS）是由NOTCH2杂合突变引起的罕见常染色体疾病，其临床特征是肢端骨溶解，严重骨质疏松，身材矮小，神经系统症状，心血管缺陷和多囊肾。最近的研究表明，异常的NOTCH2信号传导和随之而来的破骨细胞过度活跃与骨相关疾病的发病机理密切相关，但确切的分子机制仍不清楚。在这里，我们证明持续的破骨细胞活性主要是由于带有截短的C末端的NOTCH2的积累，该末端截断了FBW7介导的泛素化和降解。破骨细胞特异性Fbw7小鼠消融显示，由于Notch2信号转导升高，骨质疏松的表型使人联想到HCS。重要的是，在Fbw7条件性基因敲除小鼠中施用Notch抑制剂可减轻进行性骨吸收。这些发现突出了HCS发病机理的分子基础，并为在HCS患者中观察到的与异常FBW7 / NOTCH2途径相关的骨骼疾病的潜在靶向治疗策略提供了临床见识。