Macrophagic Sclerostin Loop2‐ApoER2 Interaction Required by Sclerostin for Cardiovascular Protective Action

作者：Luyao Wang, Xiaohui Tao, Ning Zhang, Xin Yang, Hewen Jiang, Xiaofei Li, Shenghang Wang, Shi‐Jian Ding, Sifan Yu, Huarui Zhang, Yihao Zhang, Nanxi Li, Haitian Li, Zhanghao Li, Xiaoxin Wen, Meiheng Sun, Chuanxin Zhong, Jin Liu, Yuanyuan Yu, Xiang‐Hang Luo, Tao Zhang, Shu Zhang, Péter Ferdinandy, Yuying Huang, Daqing Ma, Aiping Lü, Bao‐Ting Zhang, Ge Zhang · 发表于：Advanced Science · 年份：2025 · DOI：10.1002/advs.202518735 · 被引用次数：3 · 研究领域：Bone health and osteoporosis research、Bone Metabolism and Diseases、Osteoarthritis Treatment and Mechanisms

Abstract Therapeutic antibody against sclerostin loop2 promoted bone formation in postmenopausal osteoporosis but caused severe cardiovascular events in clinical applications. The studies of atherosclerosis and aortic aneurysm in SOST ki .ApoE −/− mice and sost −/− . ApoE −/− mice collectively indicated the cardiovascular protective action of sclerostin. However, how sclerostin exerts cardiovascular protective action remains unclear. In this study, ApoER2 (LRP8) is notably identified as a novel transmembrane receptor for sclerostin in macrophages. Mechanistically, blockade of macrophagic sclerostin loop2‐ApoER2 interaction attenuates the suppressive effects of sclerostin on NF‐κB nuclear translocation, phosphorylation, and mRNA expression in macrophages, reduces the promotive effects of sclerostin on macrophage conversion to anti‐inflammatory phenotypes, and inhibits the preventive effects of sclerostin on atherosclerosis and aortic aneurysm in ApoE −/− mice. Together, macrophagic sclerostin loop2‐ApoER2 interaction is required by sclerostin to suppress inflammatory responses, atherosclerosis, and aortic aneurysm in ApoE −/− mice. Sclerostin plays a compensatory protective role in the cardiovascular system when ApoE is absent or mutated. Translationally, it provided critical pre‐clinical evidence regarding the prediction of cardiovascular risk populations (e.g. , APOE variants) for the marketed antibody against sclerostin loop2. Importantly, targeting sclerostin while preserv...