Canonical Wnt signaling works downstream of iron overload to prevent ferroptosis from damaging osteoblast differentiation

作者全名："Luo, Cen; Xu, Wenjuan; Tang, Xun; Liu, Xinyu; Cheng, Yu; Wu, Yixun; Xie, Zhengsong; Wu, Xiaohong; He, Xin; Wang, Qian; Xiao, Yao; Qiu, Xueting; Tang, Zhurong; Shao, Gaohai; Tu, Xiaolin"

作者地址："[Luo, Cen; Xu, Wenjuan; Liu, Xinyu; Wu, Yixun; Xie, Zhengsong; Wu, Xiaohong; He, Xin; Tang, Zhurong; Tu, Xiaolin] Chongqing Med Univ, Inst Life Sci, Lab Skeletal Dev & Regenerat, Chongqing 400016, Peoples R China; [Luo, Cen; Tang, Xun; Shao, Gaohai; Tu, Xiaolin] Chongqing Med Univ, Yongchuan Hosp, Dept Orthoped, Chongqing 402160, Peoples R China; [Cheng, Yu] Chongqing Med Univ, Univ Town Hosp, Dept Nursing, Chongqing 401331, Peoples R China; [Wang, Qian; Xiao, Yao; Qiu, Xueting] Chongqing Med Univ, Sch Basic Med, Chongqing 400016, Peoples R China; [Tu, Xiaolin] Indiana Univ Sch Med, Dept Anat & Cell Biol, Indianapolis, IN 46202 USA"

通信作者："Tu, XL (通讯作者)，Chongqing Med Univ, Inst Life Sci, Lab Skeletal Dev & Regenerat, Chongqing 400016, Peoples R China.; Shao, GH; Tu, XL (通讯作者)，Chongqing Med Univ, Yongchuan Hosp, Dept Orthoped, Chongqing 402160, Peoples R China."

来源：FREE RADICAL BIOLOGY AND MEDICINE

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000830252300001

JCR分区：Q1

影响因子：7.4

年份：2022

卷号：188

期号：　

开始页：337

结束页：350

文献类型：Article

关键词：Excessiveiron; Ferroptosis; Wntsignaling; Osteoblastdifferentiation; ROS; LPO

摘要："Excessive iron has emerged in a large population of patients suffering from degenerative or hematological dis-eases with a common outcome, osteoporosis. However, its underlying mechanism remains to be clarified in order to formulate effective prevention and intervention against the loss of bone-forming osteoblasts. We show herein that increased intracellular iron by ferric ammonium citrate (FAC) mimicking the so-called non-transferrin bound iron concentrations leads to ferroptosis and impaired osteoblast differentiation. FAC upregulates the expression of Trfr and DMT1 genes to increase iron uptake, accumulating intracellular labile ferrous iron for iron overload status. Then, the excessive ferrous iron generates reactive oxygen species (ROS) and lipid peroxidation products (LPO), causing ferroptosis with its typical mitochondrial morphological changes, such as shrinkaged and condensed membrane with diminution and loss of crista and outer membrane rupture. We further examined that ferroptosis is the main cause responsible for FAC-disrupted osteoblast differentiation, although apoptosis and senescence are concurrently induced as well. Mechanistically, we revealed that iron dose-dependently down -regulates the expression of Wnt target genes and inhibits the transcription of Wnt reporter TopFlash construct, so as to inhibit the canonical Wnt signaling. Wnt agonist, ferroptosis inhibitor, or antioxidant melatonin reverses iron-inhibited canonical Wnt signaling to restore osteoblast differentiation by reducing ROS and LPO production to prevent ferroptosis notably without reducing iron overload. This study proposes a working model against excessive iron-induced osteoporosis: iron chelator deferoxamine or the above three drugs prevent ferroptosis, restore traditional Wnt signaling to maintain osteoblast differentiation no matter whether iron overload is removed or not. Additionally, iron chelator should be used to a suitable extent because iron itself is necessary for osteogenic differentiation."

基金机构："National Natural Science Foundation of China [81672118, U1601220, 82072450]; Chongqing Science and Technology Commission-Basic Science and Frontier Research Technology Special Key Project [cstc2015jcyjBX0119]"

基金资助正文："Acknowledgements We thank Prof. Ziguo Luo for TEM technical advice and support. We also thank Dr. Zhurong Tang for her writing of the manuscript in the beginning and the intellectual contribution. This work was supported by the National Natural Science Foundation of China (81672118, U1601220, 82072450) , Chongqing Science and Technology Commission-Basic Science and Frontier Research Technology Special Key Project (cstc2015jcyjBX0119) ."