@article{13f9ff8e401b4eaf816cd653b1246952,
title = "Macrophagic Sclerostin Loop2-ApoER2 Interaction Required by Sclerostin for Cardiovascular Protective Action",
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 SOSTki.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 preserving macrophagic sclerostin loop2-ApoER2 interaction would offer the next generation of precise sclerostin inhibition strategy without cardiovascular safety concern, while promoting bone formation.",
keywords = "ApoER2 (LRP8), cardiovascular events, macrophage, sclerostin",
author = "Luyao Wang and Xiaohui Tao and Ning Zhang and Xin Yang and Hewen Jiang and Xiaofei Li and Shenghang Wang and Shijian Ding and Sifan Yu and Huarui Zhang and Yihao Zhang and Nanxi Li and Haitian Li and Zhanghao Li and Xiaoxin Wen and Meiheng Sun and Chuanxin Zhong and Jin Liu and Yuanyuan Yu and Xianghang Luo and Tao Zhang and Shu Zhang and P{\'e}ter Ferdinandy and Yu Huang and Daqing Ma and Aiping Lu and Baoting Zhang and Ge Zhang",
note = "This study was supported by the National Key R\&D Program from the Ministry of Science and Technology of China (Project No. 2018YFA0800804), Hong Kong General Research Fund from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. 12102223, Project No. 12102524, Project No. 12100921, Project No. 12100725), Theme-based Research Scheme from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. T12-201/20-R), Young Scientists Fund of the National Natural Science Foundation of China (Grant No. 82300988), Shenzhen-Hong Kong-Macau Science and Technology Plan Project (Category C) (Grant No. SGDX20230821095359002), Basic and Applied Basic Research Fund from Department of Science and Technology of Guangdong Province (Project No. 2019B1515120089), Inter-institutional Collaborative Research Scheme from Hong Kong Baptist University (Project No. RC-ICRS/19-20/01), University-Industry Collaboration Programme from Innovation and Technology Commissions of the Hong Kong Special Administrative Region, China (Project No. UIM/298), University-Industry Collaboration Programme from Innovation and Technology Commissions of the Hong Kong Special Administrative Region, China (Project No. UIM/328) and Key Project of Research and Development Plan of Hunan Province (Project No. 2022WK2010). The schematic diagrams were created with BioRender.com. Publisher Copyright: {\textcopyright} 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.",
year = "2025",
month = nov,
day = "23",
doi = "10.1002/advs.202518735",
language = "English",
journal = "Advanced Science",
issn = "2198-3844",
publisher = "Wiley-VCH Verlag",
}
