A two-pronged approach to inhibit ferroptosis of MSCs caused by the iron overload in postmenopausal osteoporosis and promote osseointegration of titanium implant  

作　　者：Yulu Yang Xianhui Zhang Yao Yang Pengfei Gao Wuzhe Fan Tao Zheng Weihu Yang Yu Tang Kaiyong Cai 

机构地区：[1]Key Laboratory of Biorheological Science and Technology,Ministry of Education College of Bioengineering,Chongqing University,Chongqing,400044,China [2]Orthopedics Department,The Second Affiliated Hospital of Chongqing Medical University,Chongqing,400010,China

出　　处：《Bioactive Materials》2024年第11期336-354,共19页生物活性材料（英文）

基　　金：State Key Project of Research and Development(2022YFB3804400);National Natural Science Foundation of China(32071334,52333011&51825302);Natural Science Foundation of Chongqing(cstc2021jcyj-cxttX0002 and CSTB2023NSCQ-MSX0074);Visiting Scholar Foundation of Key Laboratory of Biorheological Science and Technology(Chongqing University);Ministry of Education(CQKLBST-2023-001).

摘　　要：Postmenopausal osteoporosis(PMOP)is a prevalent condition among elderly women.After menopause,women exhibit decreased iron excretion,which is prone to osteoporosis.To design a specific titanium implant for PMOP,we first analyze miRNAs and DNA characteristics of postmenopausal patients with and without osteoporosis.The results indicate that iron overload disrupts iron homeostasis in the pathogenesis of PMOP.Further experiments confirm that iron overload can cause lipid peroxidation and ferroptosis of MSCs,thus breaking bone homeostasis.Based on the findings above,we have designed a novel Ti implant coated with nanospheres of caffeic acid(CA)and deferoxamine(DFO).CA can bind on the Ti surface through the two adjacent phenolic hydroxyls and polymerize into polycaffeic acid(PCA)dimer,as well as the PCA nanospheres with the repetitive 1,4-benzodioxan units.DFO was grafted with PCA through borate ester bonds.The experimental results showed that modified Ti can inhibit the ferroptosis of MSCs in the pathological environment of PMOP and promote osseointegration in two main ways.Firstly,DFO was released under high oxidative stress,chelating with excess iron and decreasing the labile iron pool in MSCs.Meanwhile,CA and DFO activated the KEAP1/NRF2/HMOX1 pathway in MSCs and reduced the level of intracellular lipid peroxidation.So,the ferroptosis of MSCs is inhibited by promoting the SLC7A11/GSH/GPX4 pathway.Furthermore,the remained CA coating on the Ti surface could reduce the extracellular oxidative stress and glutathione level.This study offers a novel inspiration for the specific design of Ti implants in the treatment of PMOP.

关 键 词：Postmenopausal osteoporosis Iron overload Ferroptosis Caffeic acid nanosphere Ti implant 

分 类 号：R681[医药卫生—骨科学]