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

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 pa...

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Autores principales: Yu, Yuanyuan, Wang, Luyao, Ni, Shuaijian, Li, Dijie, Liu, Jin, Chu, Hang Yin, Zhang, Ning, Sun, Meiheng, Li, Nanxi, Ren, Qing, Zhuo, Zhenjian, Zhong, Chuanxin, Xie, Duoli, Li, Yongshu, Zhang, Zong-Kang, Zhang, Huarui, Li, Mei, Zhang, Zhenlin, Chen, Lin, Pan, Xiaohua, Xia, Weibo, Zhang, Shu, Lu, Aiping, Zhang, Bao-Ting, Zhang, Ge
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9307627/
https://www.ncbi.nlm.nih.gov/pubmed/35869074
http://dx.doi.org/10.1038/s41467-022-31997-8
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author Yu, Yuanyuan
Wang, Luyao
Ni, Shuaijian
Li, Dijie
Liu, Jin
Chu, Hang Yin
Zhang, Ning
Sun, Meiheng
Li, Nanxi
Ren, Qing
Zhuo, Zhenjian
Zhong, Chuanxin
Xie, Duoli
Li, Yongshu
Zhang, Zong-Kang
Zhang, Huarui
Li, Mei
Zhang, Zhenlin
Chen, Lin
Pan, Xiaohua
Xia, Weibo
Zhang, Shu
Lu, Aiping
Zhang, Bao-Ting
Zhang, Ge
author_facet Yu, Yuanyuan
Wang, Luyao
Ni, Shuaijian
Li, Dijie
Liu, Jin
Chu, Hang Yin
Zhang, Ning
Sun, Meiheng
Li, Nanxi
Ren, Qing
Zhuo, Zhenjian
Zhong, Chuanxin
Xie, Duoli
Li, Yongshu
Zhang, Zong-Kang
Zhang, Huarui
Li, Mei
Zhang, Zhenlin
Chen, Lin
Pan, Xiaohua
Xia, Weibo
Zhang, Shu
Lu, Aiping
Zhang, Bao-Ting
Zhang, Ge
author_sort Yu, Yuanyuan
collection PubMed
description 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.
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spelling pubmed-93076272022-07-24 Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation Yu, Yuanyuan Wang, Luyao Ni, Shuaijian Li, Dijie Liu, Jin Chu, Hang Yin Zhang, Ning Sun, Meiheng Li, Nanxi Ren, Qing Zhuo, Zhenjian Zhong, Chuanxin Xie, Duoli Li, Yongshu Zhang, Zong-Kang Zhang, Huarui Li, Mei Zhang, Zhenlin Chen, Lin Pan, Xiaohua Xia, Weibo Zhang, Shu Lu, Aiping Zhang, Bao-Ting Zhang, Ge Nat Commun Article 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. Nature Publishing Group UK 2022-07-22 /pmc/articles/PMC9307627/ /pubmed/35869074 http://dx.doi.org/10.1038/s41467-022-31997-8 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Yu, Yuanyuan
Wang, Luyao
Ni, Shuaijian
Li, Dijie
Liu, Jin
Chu, Hang Yin
Zhang, Ning
Sun, Meiheng
Li, Nanxi
Ren, Qing
Zhuo, Zhenjian
Zhong, Chuanxin
Xie, Duoli
Li, Yongshu
Zhang, Zong-Kang
Zhang, Huarui
Li, Mei
Zhang, Zhenlin
Chen, Lin
Pan, Xiaohua
Xia, Weibo
Zhang, Shu
Lu, Aiping
Zhang, Bao-Ting
Zhang, Ge
Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation
title Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation
title_full Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation
title_fullStr Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation
title_full_unstemmed Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation
title_short Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation
title_sort targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9307627/
https://www.ncbi.nlm.nih.gov/pubmed/35869074
http://dx.doi.org/10.1038/s41467-022-31997-8
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