Magnesium implantation or supplementation ameliorates bone disorder in CFTR-mutant mice through an ATF4-dependent Wnt/β-catenin signaling

Magnesium metal and its alloys are being developed as effective orthopedic implants; however, the mechanisms underlying the actions of magnesium on bones remain unclear. Cystic fibrosis, the most common genetic disease in Caucasians caused by the mutation of CFTR, has shown bone disorder as a key cl...

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Autores principales:	Jiankun Xu, Peijie Hu, Xiaotian Zhang, Junjiang Chen, Jiali Wang, Jieting Zhang, Ziyi Chen, Mei Kuen Yu, Yiu Wa Chung, Yan Wang, Xiaohu Zhang, Yifeng Zhang, Nianye Zheng, Hao Yao, Jiang Yue, Hsiao Chang Chan, Ling Qin, Ye Chun Ruan
Formato:	article
Lenguaje:	EN
Publicado:	KeAi Communications Co., Ltd. 2022
Materias:	Magnesium implant Cystic fibrosis-related bone disorder ATF4 Wnt/β-catenin signaling Materials of engineering and construction. Mechanics of materials TA401-492 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/657116a1f8ca4ad3ba44165885c680ae
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spelling	oai:doaj.org-article:657116a1f8ca4ad3ba44165885c680ae2021-11-04T04:36:20ZMagnesium implantation or supplementation ameliorates bone disorder in CFTR-mutant mice through an ATF4-dependent Wnt/β-catenin signaling2452-199X10.1016/j.bioactmat.2021.06.034https://doaj.org/article/657116a1f8ca4ad3ba44165885c680ae2022-02-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2452199X21003200https://doaj.org/toc/2452-199XMagnesium metal and its alloys are being developed as effective orthopedic implants; however, the mechanisms underlying the actions of magnesium on bones remain unclear. Cystic fibrosis, the most common genetic disease in Caucasians caused by the mutation of CFTR, has shown bone disorder as a key clinical manifestation, which currently lacks effective therapeutic options. Here we report that implantation of magnesium-containing implant stimulates bone formation and improves bone fracture healing in CFTR-mutant mice. Wnt/β-catenin signaling in the bone is enhanced by the magnesium implant, and inhibition of Wnt/β-catenin by iCRT14 blocks the magnesium implant to improve fracture healing in CFTR-mutant mice. We further demonstrate that magnesium ion enters osteocytes, increases intracellular cAMP level and activates ATF4, a key transcription factor known to regulate Wnt/β-catenin signaling. In vivo knockdown of ATF4 abolishes the magnesium implant-activated β-catenin in bones and reverses the improved-fracture healing in CFTR-mutant mice. In addition, oral supplementation of magnesium activates ATF4 and β-catenin as well as enhances bone volume and density in CFTR-mutant mice. Together, these results show that magnesium implantation or supplementation may serve as a potential anabolic therapy for cystic fibrosis-related bone disease. Activation of ATF4-dependent Wnt/β-catenin signaling in osteocytes is identified as a previously undefined mechanism underlying the beneficial effect of magnesium on bone formation.Jiankun XuPeijie HuXiaotian ZhangJunjiang ChenJiali WangJieting ZhangZiyi ChenMei Kuen YuYiu Wa ChungYan WangXiaohu ZhangYifeng ZhangNianye ZhengHao YaoJiang YueHsiao Chang ChanLing QinYe Chun RuanKeAi Communications Co., Ltd.articleMagnesium implantCystic fibrosis-related bone disorderATF4Wnt/β-catenin signalingMaterials of engineering and construction. Mechanics of materialsTA401-492Biology (General)QH301-705.5ENBioactive Materials, Vol 8, Iss , Pp 95-108 (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Magnesium implant Cystic fibrosis-related bone disorder ATF4 Wnt/β-catenin signaling Materials of engineering and construction. Mechanics of materials TA401-492 Biology (General) QH301-705.5
spellingShingle	Magnesium implant Cystic fibrosis-related bone disorder ATF4 Wnt/β-catenin signaling Materials of engineering and construction. Mechanics of materials TA401-492 Biology (General) QH301-705.5 Jiankun Xu Peijie Hu Xiaotian Zhang Junjiang Chen Jiali Wang Jieting Zhang Ziyi Chen Mei Kuen Yu Yiu Wa Chung Yan Wang Xiaohu Zhang Yifeng Zhang Nianye Zheng Hao Yao Jiang Yue Hsiao Chang Chan Ling Qin Ye Chun Ruan Magnesium implantation or supplementation ameliorates bone disorder in CFTR-mutant mice through an ATF4-dependent Wnt/β-catenin signaling
description	Magnesium metal and its alloys are being developed as effective orthopedic implants; however, the mechanisms underlying the actions of magnesium on bones remain unclear. Cystic fibrosis, the most common genetic disease in Caucasians caused by the mutation of CFTR, has shown bone disorder as a key clinical manifestation, which currently lacks effective therapeutic options. Here we report that implantation of magnesium-containing implant stimulates bone formation and improves bone fracture healing in CFTR-mutant mice. Wnt/β-catenin signaling in the bone is enhanced by the magnesium implant, and inhibition of Wnt/β-catenin by iCRT14 blocks the magnesium implant to improve fracture healing in CFTR-mutant mice. We further demonstrate that magnesium ion enters osteocytes, increases intracellular cAMP level and activates ATF4, a key transcription factor known to regulate Wnt/β-catenin signaling. In vivo knockdown of ATF4 abolishes the magnesium implant-activated β-catenin in bones and reverses the improved-fracture healing in CFTR-mutant mice. In addition, oral supplementation of magnesium activates ATF4 and β-catenin as well as enhances bone volume and density in CFTR-mutant mice. Together, these results show that magnesium implantation or supplementation may serve as a potential anabolic therapy for cystic fibrosis-related bone disease. Activation of ATF4-dependent Wnt/β-catenin signaling in osteocytes is identified as a previously undefined mechanism underlying the beneficial effect of magnesium on bone formation.
format	article
author	Jiankun Xu Peijie Hu Xiaotian Zhang Junjiang Chen Jiali Wang Jieting Zhang Ziyi Chen Mei Kuen Yu Yiu Wa Chung Yan Wang Xiaohu Zhang Yifeng Zhang Nianye Zheng Hao Yao Jiang Yue Hsiao Chang Chan Ling Qin Ye Chun Ruan
author_facet	Jiankun Xu Peijie Hu Xiaotian Zhang Junjiang Chen Jiali Wang Jieting Zhang Ziyi Chen Mei Kuen Yu Yiu Wa Chung Yan Wang Xiaohu Zhang Yifeng Zhang Nianye Zheng Hao Yao Jiang Yue Hsiao Chang Chan Ling Qin Ye Chun Ruan
author_sort	Jiankun Xu
title	Magnesium implantation or supplementation ameliorates bone disorder in CFTR-mutant mice through an ATF4-dependent Wnt/β-catenin signaling
title_short	Magnesium implantation or supplementation ameliorates bone disorder in CFTR-mutant mice through an ATF4-dependent Wnt/β-catenin signaling
title_full	Magnesium implantation or supplementation ameliorates bone disorder in CFTR-mutant mice through an ATF4-dependent Wnt/β-catenin signaling
title_fullStr	Magnesium implantation or supplementation ameliorates bone disorder in CFTR-mutant mice through an ATF4-dependent Wnt/β-catenin signaling
title_full_unstemmed	Magnesium implantation or supplementation ameliorates bone disorder in CFTR-mutant mice through an ATF4-dependent Wnt/β-catenin signaling
title_sort	magnesium implantation or supplementation ameliorates bone disorder in cftr-mutant mice through an atf4-dependent wnt/β-catenin signaling
publisher	KeAi Communications Co., Ltd.
publishDate	2022
url	https://doaj.org/article/657116a1f8ca4ad3ba44165885c680ae
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Magnesium implantation or supplementation ameliorates bone disorder in CFTR-mutant mice through an ATF4-dependent Wnt/β-catenin signaling

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