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

doi:10.1002/advs.202518735

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

Luyao Wang^* (Co-first Author)
, Xiaohui Tao (Co-first Author)
, Ning Zhang (Co-first Author)
, Xin Yang (Co-first Author)
, Hewen Jiang (Co-first Author)
, 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^*

^*Corresponding author for this work

Department of Biomedical Sciences

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

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. © 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.

Original language	English
Article number	e18735
Journal	Advanced Science
DOIs	https://doi.org/10.1002/advs.202518735
Publication status	Online published - 23 Nov 2025

Funding

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\u2010based Research Scheme from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. T12\u2010201/20\u2010R), Young Scientists Fund of the National Natural Science Foundation of China (Grant No. 82300988), Shenzhen\u2010Hong Kong\u2010Macau 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\u2010institutional Collaborative Research Scheme from Hong Kong Baptist University (Project No. RC\u2010ICRS/19\u201020/01), University\u2010Industry Collaboration Programme from Innovation and Technology Commissions of the Hong Kong Special Administrative Region, China (Project No. UIM/298), University\u2010Industry 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.

Research Keywords

ApoER2 (LRP8)
cardiovascular events
macrophage
sclerostin

RGC Funding Information

RGC-funded

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10.1002/advs.202518735

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Wang, L., Tao, X., Zhang, N., Yang, X., Jiang, H., Li, X., Wang, S., Ding, S., Yu, S., Zhang, H., Zhang, Y., Li, N., Li, H., Li, Z., Wen, X., Sun, M., Zhong, C., Liu, J., Yu, Y., ... Zhang, G. (2025). Macrophagic Sclerostin Loop2-ApoER2 Interaction Required by Sclerostin for Cardiovascular Protective Action. Advanced Science, Article e18735. Advance online publication. https://doi.org/10.1002/advs.202518735

@article{a6b6ea8d7b8248e2beccdbdb23268019,

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. {\textcopyright} 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.",

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",

year = "2025",

month = nov,

day = "23",

doi = "10.1002/advs.202518735",

language = "English",

journal = "Advanced Science",

issn = "2198-3844",

publisher = "Wiley-VCH Verlag GmbH",

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Wang, L, Tao, X, Zhang, N, Yang, X, Jiang, H, Li, X, Wang, S, Ding, S, Yu, S, Zhang, H, Zhang, Y, Li, N, Li, H, Li, Z, Wen, X, Sun, M, Zhong, C, Liu, J, Yu, Y, Luo, X, Zhang, T, Zhang, S, Ferdinandy, P, Huang, Y, Ma, D, Lu, A, Zhang, B & Zhang, G 2025, 'Macrophagic Sclerostin Loop2-ApoER2 Interaction Required by Sclerostin for Cardiovascular Protective Action', Advanced Science. https://doi.org/10.1002/advs.202518735

TY - JOUR

T1 - Macrophagic Sclerostin Loop2-ApoER2 Interaction Required by Sclerostin for Cardiovascular Protective Action

AU - Wang, Luyao

AU - Tao, Xiaohui

AU - Zhang, Ning

AU - Yang, Xin

AU - Jiang, Hewen

AU - Li, Xiaofei

AU - Wang, Shenghang

AU - Ding, Shijian

AU - Yu, Sifan

AU - Zhang, Huarui

AU - Zhang, Yihao

AU - Li, Nanxi

AU - Li, Haitian

AU - Li, Zhanghao

AU - Wen, Xiaoxin

AU - Sun, Meiheng

AU - Zhong, Chuanxin

AU - Liu, Jin

AU - Yu, Yuanyuan

AU - Luo, Xianghang

AU - Zhang, Tao

AU - Zhang, Shu

AU - Ferdinandy, Péter

AU - Huang, Yu

AU - Ma, Daqing

AU - Lu, Aiping

AU - Zhang, Baoting

AU - Zhang, Ge

PY - 2025/11/23

Y1 - 2025/11/23

N2 - 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. © 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.

AB - 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. © 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.

KW - ApoER2 (LRP8)

KW - cardiovascular events

KW - macrophage

KW - sclerostin

UR - https://www.scopus.com/pages/publications/105022699494

UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-105022699494&origin=recordpage

UR - https://www.webofscience.com/wos/woscc/full-record/WOS:001620483700001

U2 - 10.1002/advs.202518735

DO - 10.1002/advs.202518735

M3 - RGC 21 - Publication in refereed journal

SN - 2198-3844

JO - Advanced Science

JF - Advanced Science

M1 - e18735

ER -

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

Abstract

Funding

Research Keywords

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