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

Yu，Yuanyuan1,2,3,4; Wang，Luyao1,2,3,4; Ni，Shuaijian1,2,3,4; Li，Dijie1,2,3,4; Liu，Jin1,2,3,4; Chu，Hang Yin2,5; Zhang，Ning2,5; Sun，Meiheng1,2,3,4; Li，Nanxi1,2,3,4; Ren，Qing1,2,3,4; Zhuo，Zhenjian2,5; Zhong，Chuanxin1,2,3,4,6; Xie，Duoli1,2,3,4; Li，Yongshu1,2,3,4; Zhang，Zong Kang2,5; Zhang，Huarui1,2,3,4; Li，Mei7; Zhang，Zhenlin8; Chen，Lin9; Pan，Xiaohua10; Xia，Weibo7; Zhang，Shu11; Lu，Aiping1,2,3,4; Zhang，Bao Ting2,5; Zhang，Ge1,2,3,4

2022-07-22

10.1038/s41467-022-31997-8

NATURE COMMUNICATIONS   Impact Factor & Quartile

2041-1723

["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 hSOST(ki).ApoE(-/-) mice with angiotensin II infusion. Apc001PE can promote bone formation in hSOST(ki) mice and ovariectomy-induced osteoporotic rats. In summary, sclerostin loop3 cannot participate in protecting the cardiovascular system, but participates in inhibiting bone formation.","Antibodies targeting sclerostin can ameliorate postmenopausal osteoporosis but present some cardiovascular risk. Here the authors show that the cardiovascular and skeletal effects of sclerostin are mediated by different loops, suggesting ways to preserve the positive effects on bone formation while avoiding the negative cardiovascular consequences."]

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National Key R&D Program from the Ministry of Science and Technology of China[2018YFA0800800] ; Hong Kong General Research Fund from the Research Grants Council of the Hong Kong Special Administrative Region, China["12102120","12114416","12100921","12103519","12136616","14103420","14103121","14109721"] ; Theme-based Research Scheme from the Research Grants Council of the Hong Kong Special Administrative Region, China[T12-201/20-R] ; Basic and Applied Basic Research Fund from Department of Science and Technology of Guangdong Province[2019B1515120089] ; Inter-institutional Collaborative Research Scheme from Hong Kong Baptist University[RC-ICRS/19-20/01] ; University-Industry Collaboration Programme from Innovation and Technology Commissions of the Hong Kong Special Administrative Region, China["UIM/328","UIM/298"]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:000829110700004

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2-s2.0-85134618575

Web of Science

1.Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ),School of Chinese Medicine,Hong Kong Baptist University,Hong Kong
2.Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP),Hong Kong
3.Institute of Precision Medicine and Innovative Drug Discovery (PMID),School of Chinese Medicine,Hong Kong Baptist University,Hong Kong
4.Institute of Integrated Bioinformedicine and Translational Science (IBTS),School of Chinese Medicine,Hong Kong Baptist University,Hong Kong
5.School of Chinese Medicine,Faculty of Medicine,The Chinese University of Hong Kong,Hong Kong
6.Department of Materials Science and Engineering,Southern University of Science and Technology,Shenzhen,China
7.Department of Endocrinology,National Health Commission Key Laboratory of Endocrinology,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China
8.Shanghai Clinical Research Center of Bone Disease,Department of Osteoporosis and Bone Disease,Shanghai Jiao Tong University Affiliated Sixth People’s Hospital,Shanghai,China
9.Department of Wound Repair and Rehabilitation Medicine,State Key Laboratory of Trauma,Burns and Combined Injury,Trauma Center,Research Institute of Surgery,Daping Hospital,Army Medical University,Chongqing,China
10.Orthopedic Center,The Second Affiliated Hospital of Shenzhen University (People’s Hospital of Shenzhen Baoan District),Shenzhen,China
11.The Key Laboratory of Aerospace Medicine,Ministry of Education,Air Force Medical University,Xi’an,Shaanxi,China

Yu，Yuanyuan,Wang，Luyao,Ni，Shuaijian,et al. Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation[J]. NATURE COMMUNICATIONS,2022,13(1).

Yu，Yuanyuan.,Wang，Luyao.,Ni，Shuaijian.,Li，Dijie.,Liu，Jin.,...&Zhang，Ge.(2022).Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation.NATURE COMMUNICATIONS,13(1).

Yu，Yuanyuan,et al."Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation".NATURE COMMUNICATIONS 13.1(2022).