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journal article·2026-02Open access

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

Luyao Wang, Xiaohui Tao, Ning Zhang, Xin Yang, Hewen Jiang, Xiaofei Li, Shenghang Wang, Shijian Ding, Sifan Yu, Huarui Zhang, Yihao Zhang, Nanxi Li, Haitian Li, Zhanghao Li, Xiaoxin Wen, Meiheng Sun, Chuanxin Zhong, Jin Liu, Yuanyuan Yu, Xianghang Luo, Tao Zhang, Shu Zhang, Péter Ferdinandy, Yu Huang, Daqing Ma, Aiping Lu, Baoting Zhang, Ge Zhang

Advanced Science· Volume 13· Issue 8
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Abstract

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 preserving macrophagic sclerostin loop2‐ApoER2 interaction would offer the next generation of precise sclerostin inhibition strategy without cardiovascular safety concern, while promoting bone formation.
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Research context

OpenAlex topics: Bone health and osteoporosis research · Bone Metabolism and Diseases · Osteoarthritis Treatment and Mechanisms

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ) School of Chinese Medicine Hong Kong Baptist University Hong Kong SAR 000000 China

Guangdong‐Hong Kong‐Macao Greater Bay Area International Research Platform for Aptamer‐based Translational Medicine and Drug Discovery (HKAP) Hong Kong SAR 000000 China

Institute of Precision Medicine and Innovative Drug Discovery (PMID) School of Chinese Medicine Hong Kong Baptist University Hong Kong SAR 000000 China

Institute of Integrated Bioinformedicine and Translational Science (IBTS) School of Chinese Medicine Hong Kong Baptist University Hong Kong SAR 000000 China

School of Chinese Medicine Faculty of Medicine The Chinese University of Hong Kong Hong Kong SAR 000000 China

Xiangya Hospital of Central South University Hunan 410008 China

Shanghai Institute of Technical Physics Chinese Academy of Sciences Shanghai 200083 China

The Key Laboratory of Aerospace Medicine Ministry of Education Air Force Medical University Xi'an Shanxi 710000 China

Department of Pharmacology and Pharmacotherapy Semmelweis University Budapest 1007 Hungary

Center for Pharmacology and Drug Research and Development Semmelweis University Budapest 1007 Hungary

Pharmahungary Group Szeged 6700 Hungary

Biomedical Sciences and Vascular Biology City University of Hong Kong Hong Kong SAR 000000 China

Perioperative and Systems Medicine Laboratory and Department of Anesthesiology Children's Hospital Zhejiang University School of Medicine National Clinical Research Centre for Child Health Hangzhou 242332 China

Division of Anaesthetics Pain Medicine and Intensive Care Department of Surgery and Cancer Faculty of Medicine Imperial College London Chelsea and Westminster Hospital London E1 7AD UK

Funding

National Natural Science Foundation of China · Key Project of Research and Development Plan of Hunan Province · University Grants Committee

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