Blocking interaction of sclerostin loop3 with osteoblastic LRP4 counteracts bone loss without increasing arterial stiffness during mechanical unloading

作者：Luyao Wang, Ning Zhang, Hewen Jiang, Xiaohui Tao, Yuan Ma, Zebing Hu, Chuanxin Zhong, Xin Yang, Sifan Yu, Huarui Zhang, Liu Jin, Yuanyuan Yu, Fangwu Liu, Zefeng Chen, Hang Luo, Shijian Ding, Yihao Zhang, Meiheng Sun, Shiqing Zhang, Shiqing Zhang, Péter Ferdinandy, Rongjun Yu, Tao Zhang, Aiping Lu, Ling Qin, BaoTing Zhang, Ge Zhang, BaoTing Zhang, Ge Zhang · 发表于：Journal of Orthopaedic Translation · 年份：2026 · DOI：10.1016/j.jot.2026.101117 · 被引用次数：2 · 研究领域：Bone health and osteoporosis research、Cardiomyopathy and Myosin Studies、Bone Metabolism and Diseases

Background Mechanical unloading leads to bone loss and cardiovascular deconditioning, accompanied by elevated sclerostin expression. Genetic Sost knockout or pharmacologic sclerostin antibody treatment was reported to counteract bone loss during mechanical unloading in mice. However, severe cardiovascular events were reported in postmenopausal osteoporotic patients treated with commercially available sclerostin antibody targeting loop2. It is desirable to develop a precise sclerostin inhibition strategy to counteract unloading-induced bone loss, without increasing cardiovascular risk. Methods and results In a previously published rodent studies under normal loading condition, it was found that sclerostin loop3 participated in the inhibitory effect of sclerostin on bone formation, while the preventive action of sclerostin against cardiovascular events was independent of sclerostin loop3. Nevertheless, whether and how sclerostin loop3 contributes to bone formation reduction and bone loss under mechanical unloading condition remains unclear. In this study under mechanical unloading condition, either sclerostin loop3-specific deficiency in Sost loop3−/ − mice or sclerostin loop3-specific inhibition by our tailor-made aptamer Apc001 counteracted unloading-induced bone loss without increasing arterial stiffness, whereas either Sost knockout or romosozumab treatment significantly increased unloading-induced arterial stiffness in mice. These findings indicated sclerostin loop3 as a t...