Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation

Yuanyuan Yu*, Luyao Wang, Shuaijian Ni, Dijie Li, Jin Liu, Hang Yin Chu, Ning Zhang, Meiheng Sun, Nanxi Li, Qing Ren, Zhenjian Zhuo, Chuanxin Zhong, Duoli Xie, Yongshu Li, Zong Kang Zhang, Huarui Zhang, Mei Li, Zhenlin Zhang, Lin Chen, Xiaohua PanWeibo Xia, Shu Zhang, Aiping Lu*, Bao Ting Zhang*, Ge Zhang*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

40 Citations (Scopus)

Abstract

Sclerostin negatively regulates bone formation by antagonizing Wnt signalling. An antibody targeting sclerostin for the treatment of postmenopausal osteoporosis was approved by the U.S. Food and Drug Administration, with a boxed warning for cardiovascular risk. Here we demonstrate that sclerostin participates in protecting cardiovascular system and inhibiting bone formation via different loops. Loop3 deficiency by genetic truncation could maintain sclerostin’s protective effect on the cardiovascular system while attenuating its inhibitory effect on bone formation. We identify an aptamer, named aptscl56, which specifically targets sclerostin loop3 and use a modified aptscl56 version, called Apc001PE, as specific in vivo pharmacologic tool to validate the above effect of loop3. Apc001PE has no effect on aortic aneurysm and atherosclerotic development in ApoE−/− mice and hSOSTki.ApoE−/− mice with angiotensin II infusion. Apc001PE can promote bone formation in hSOSTki mice and ovariectomy-induced osteoporotic rats. In summary, sclerostin loop3 cannot participate in protecting the cardiovascular system, but participates in inhibiting bone formation.

Original languageEnglish
Article number4241
Number of pages16
JournalNature Communications
Volume13
DOIs
Publication statusPublished - 22 Jul 2022

Scopus Subject Areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)

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