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<p>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 <i>Lrp4</i> mutation (<i>Lrp4m</i>) and blocking peptide (LRP4-Pep) diminished the antagonistic effect of sclerostin on Wnt/β-catenin signaling in osteoblasts in vitro. Consistently, <i>Lrp4m</i> promoted bone formation in <i>Lrp4m</i> mice in vivo. Mechanistically, osteoblast-conditional correction of <i>Lrp4m</i> to wild-type <i>Lrp4</i> resulted in significantly lower bone formation than <i>Lrp4m</i> mice, indicating that the promotive effects of <i>Lrp4m</i> on bone formation acted in osteoblasts in vivo. Moreover, re-expression of sclerostin dramatically inhibited bone formation in <i>sost</i><sup><i>−/−</i></sup> mice, whilst the inhibitory effects of sclerostin were significantly weaker in <i>sost</i><sup><i>−/−</i></sup><i>.Lrp4m</i> mice. Pharmacologically, LRP4-Pep diminished the inhibitory effects of sclerostin on bone formation in <i>SOST</i><sup><i>ki</i></sup> 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.</p>

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Osteoblastic sclerostin loop3-LRP4 interaction required by sclerostin to inhibit bone formation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月24日

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  • 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

摘要

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.