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

• Published in: Bioactive materials 2022-02, Vol.8, p.95-108
• Main Authors: Xu, Jiankun, Hu, Peijie, Zhang, Xiaotian, Chen, Junjiang, Wang, Jiali, Zhang, Jieting, Chen, Ziyi, Yu, Mei Kuen, Chung, Yiu Wa, Wang, Yan, Zhang, Xiaohu, Zhang, Yifeng, Zheng, Nianye, Yao, Hao, Yue, Jiang, Chan, Hsiao Chang, Qin, Ling, Ruan, Ye Chun
• Format: Article
• Language: English
• Subjects: ATF4; Cystic fibrosis-related bone disorder; Magnesium implant; Wnt/β-catenin signaling
• ISSN: 2452-199X; 2452-199X
• DOI: 10.1016/j.bioactmat.2021.06.034

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. Schematic diagram showing the effect of magnesium on bone formation with CFTR deficiency. Entering bone forming cells through Mg2+ channels or transporters, Mg2+ induces cAMP increase and the activation of transcription factors, ATF4 and β-catenin (β-Cat), rescuing CFTR deficiency-impaired Wnt/β-catenin signaling to promote bone formation. [Display omitted] •Magnesium implant ameliorates bone defects and improves the impaired bone fracture healing in CFTR-deficient mice.•Oral magnesium supplementation improves bone quality in CFTR-deficient mice.•Extracellular Mg2+ enters bone cells through Mg2+ channels and transporters.•Mg2+ elevates cAMP level to activate ATF4-dependent Wnt/β-catenin signalingin bone cells.