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...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.展开更多
基金supported in part by Theme-based Research Scheme of Hong Kong(No.T13-402/17 N)Health and Medical Research Fund of Hong Kong(15161441 and 18190481)+3 种基金Early Career Scheme of Hong Kong(No.24104517)Start-up fund at the Hong Kong Polytechnic UniversityNational Natural Science Foundation of China(81802152)Natural Science Foundation of Guangdong Province(2019A1515012224 and 2021A1515011204).
文摘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.
