Osteoblastic sclerostin loop3-LRP4 interaction required by sclerostin to inhibit bone formationOA
Sclerostin negatively regulates bone formation.The marketed antibody against sclerostin loop2 promoted bone formation but may have caused severe cardiovascular events in clinical use.In our published studies,sclerostin loop3 was found to be involved in inhibitory effects of sclerostin on bone formation,whereas cardiovascular protective effects of sclerostin in mice were independent of loop3.It is necessary to investigate how sclerostin loop3 participates in the inhibitory effects of sclerostin on bone formation to facilitate developing precise strategies that promote bone formation without increasing cardiovascular risk.In this study,sclerostin loop3 was identified to bind to LRP4,thereby facilitating binding of sclerostin to LRP6 in osteoblasts.Blockade of sclerostin loop3-LRP4 interaction by both Lrp4 mutation(Lrp4m)and blocking peptide(LRP4-Pep)diminished the antagonistic effect of sclerostin on Wnt/β-catenin signaling in osteoblasts in vitro.Consistently,Lrp4m promoted bone formation in Lrp4m mice in vivo.Mechanistically,osteoblast-conditional correction of Lrp4m to wild-type Lrp4 resulted in significantly lower bone formation than Lrp4m mice,indicating that the promotive effects of Lrp4m on bone formation acted in osteoblasts in vivo.Moreover,re-expression of sclerostin dramatically inhibited bone formation in sost−/−mice,whilst the inhibitory effects of sclerostin were significantly weaker in sost−/−.Lrp4m mice.Pharmacologically,LRP4-Pep diminished the inhibitory effects of sclerostin on bone formation in SOSTki mice.Taken together,osteoblastic sclerostin loop3-LRP4 interaction,as an anchor,was required by sclerostin to bind to LRP6,thereby inhibiting bone formation.Translationally,blockade of sclerostin loop3-LRP4 interaction in osteoblasts would provide precise therapeutic strategies to promote bone formation without increasing cardiovascular risk.
Luyao Wang;Xiaohui Tao;Hewen Jiang;Shijian Ding;Ning Zhang;Xin Yang;Shenghang Wang;Yihao Zhang;Nanxi Li;Haitian Li;Zhanghao Li;Xiaoxin Wen;Meiheng Sun;Chuanxin Zhong;Heiwa So;Jin Liu;Yuanyuan Yu;Hua Yue;Xianghang Luo;Péter Ferdinandy;Tao Zhang;Shu Zhang;Zhenlin Zhang;Aiping Lu;Baoting Zhang;Ge Zhang
Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases(TMBJ),Hong Kong Baptist University,Hong Kong SAR,China Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery(HKAP),Hong Kong SAR,China Institute of Integrated Bioinformedicine and Translational Science(IBTS),Hong Kong Baptist University,Hong Kong SAR,ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases(TMBJ),Hong Kong Baptist University,Hong Kong SAR,China Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery(HKAP),Hong Kong SAR,China Institute of Integrated Bioinformedicine and Translational Science(IBTS),Hong Kong Baptist University,Hong Kong SAR,ChinaSchool of Chinese Medicine,Faculty of Medicine,The Chinese University of Hong Kong,Hong Kong SAR,ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases(TMBJ),Hong Kong Baptist University,Hong Kong SAR,China Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery(HKAP),Hong Kong SAR,China Institute of Integrated Bioinformedicine and Translational Science(IBTS),Hong Kong Baptist University,Hong Kong SAR,ChinaSchool of Chinese Medicine,Faculty of Medicine,The Chinese University of Hong Kong,Hong Kong SAR,ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases(TMBJ),Hong Kong Baptist University,Hong Kong SAR,China Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery(HKAP),Hong Kong SAR,China Institute of Integrated Bioinformedicine and Translational Science(IBTS),Hong Kong Baptist University,Hong Kong SAR,ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases(TMBJ),Hong Kong Baptist University,Hong Kong SAR,China Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery(HKAP),Hong Kong SAR,China Institute of Integrated Bioinformedicine and Translational Science(IBTS),Hong Kong Baptist University,Hong Kong SAR,ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases(TMBJ),Hong Kong Baptist University,Hong Kong SAR,China Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery(HKAP),Hong Kong SAR,China Institute of Integrated Bioinformedicine and Translational Science(IBTS),Hong Kong Baptist University,Hong Kong SAR,ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases(TMBJ),Hong Kong Baptist University,Hong Kong SAR,China Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery(HKAP),Hong Kong SAR,China Institute of Integrated Bioinformedicine and Translational Science(IBTS),Hong Kong Baptist University,Hong Kong SAR,ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases(TMBJ),Hong Kong Baptist University,Hong Kong SAR,China Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery(HKAP),Hong Kong SAR,China Institute of Integrated Bioinformedicine and Translational Science(IBTS),Hong Kong Baptist University,Hong Kong SAR,ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases(TMBJ),Hong Kong Baptist University,Hong Kong SAR,China Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery(HKAP),Hong Kong SAR,China Institute of Integrated Bioinformedicine and Translational Science(IBTS),Hong Kong Baptist University,Hong Kong SAR,ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases(TMBJ),Hong Kong Baptist University,Hong Kong SAR,China Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery(HKAP),Hong Kong SAR,China Institute of Integrated Bioinformedicine and Translational Science(IBTS),Hong Kong Baptist University,Hong Kong SAR,ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases(TMBJ),Hong Kong Baptist University,Hong Kong SAR,China Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery(HKAP),Hong Kong SAR,China Institute of Integrated Bioinformedicine and Translational Science(IBTS),Hong Kong Baptist University,Hong Kong SAR,ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases(TMBJ),Hong Kong Baptist University,Hong Kong SAR,China Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery(HKAP),Hong Kong SAR,China Institute of Integrated Bioinformedicine and Translational Science(IBTS),Hong Kong Baptist University,Hong Kong SAR,ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases(TMBJ),Hong Kong Baptist University,Hong Kong SAR,China Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery(HKAP),Hong Kong SAR,China Institute of Integrated Bioinformedicine and Translational Science(IBTS),Hong Kong Baptist University,Hong Kong SAR,ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases(TMBJ),Hong Kong Baptist University,Hong Kong SAR,China Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery(HKAP),Hong Kong SAR,China Institute of Integrated Bioinformedicine and Translational Science(IBTS),Hong Kong Baptist University,Hong Kong SAR,ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases(TMBJ),Hong Kong Baptist University,Hong Kong SAR,China Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery(HKAP),Hong Kong SAR,China Institute of Integrated Bioinformedicine and Translational Science(IBTS),Hong Kong Baptist University,Hong Kong SAR,ChinaDepartment of Osteoporosis and Bone Diseases,Shanghai Clinical Research Center of Bone Diseases,Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai,ChinaXiangya Hospital of Central South University,Hu Nan,ChinaDepartment of Pharmacology and Pharmacotherapy,Semmelweis University,Budapest,HungaryShanghai Institute of Technical Physics Chinese Academy of Sciences,Shanghai,ChinaThe Key Laboratory of Aerospace Medicine,Ministry of Education,Air Force Medical University,Xi’an,Shanxi,ChinaDepartment of Osteoporosis and Bone Diseases,Shanghai Clinical Research Center of Bone Diseases,Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai,ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases(TMBJ),Hong Kong Baptist University,Hong Kong SAR,China Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery(HKAP),Hong Kong SAR,China Institute of Integrated Bioinformedicine and Translational Science(IBTS),Hong Kong Baptist University,Hong Kong SAR,ChinaSchool of Chinese Medicine,Faculty of Medicine,The Chinese University of Hong Kong,Hong Kong SAR,ChinaLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases(TMBJ),Hong Kong Baptist University,Hong Kong SAR,China Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery(HKAP),Hong Kong SAR,China Institute of Integrated Bioinformedicine and Translational Science(IBTS),Hong Kong Baptist University,Hong Kong SAR,China
医药卫生
Wnt catenin signalingosteoblastic interactionsclerostin loopbone formationLRPcardiovascular risk
《Bone Research》 2026 (3)
P.949-962,14
supported by the National Key R&D Program from the Ministry of Science and Technology of China(Project No.2024YFE0216100,Project No.MHP/314/24,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-Macao Science and Technology Plan Project(Category C)(Grant No.SGDX20230821095359002)National Natural Science Foundation of China(Grant No.82270932)Shanghai Sixth People’s Hospital High-level Talent Support Cultivation Programme Project(Project No.ynljzc202408)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)Shanghai Research Center for Endocrine and Metabolic Diseases(Project No.2022ZZ01002)Key Project of Research and Development Plan of Hunan Province(Project No.2022WK2010).
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