Neural EGFL-like 2(NELL2)is a secreted protein known for its regulatory functions in the nervous and reproductive systems,yet its role in bone biology remains unexplored.In this study,we observed that NELL2 was dimini...Neural EGFL-like 2(NELL2)is a secreted protein known for its regulatory functions in the nervous and reproductive systems,yet its role in bone biology remains unexplored.In this study,we observed that NELL2 was diminished in the bone of aged and ovariectomized(OVX)mice,as well as in the serum of osteopenia and osteoporosis patients.In vitro loss-of-function and gain-offunction studies revealed that NELL2 facilitated osteoblast differentiation and impeded adipocyte differentiation from stromal progenitor cells.In vivo studies further demonstrated that the deletion of NELL2 in preosteoblasts resulted in decreased cancellous bone mass in mice.Mechanistically,NELL2 interacted with the FNI-type domain located at the C-terminus of Fibronectin 1(Fn1).Moreover,we found that NELL2 activated the focal adhesion kinase(FAK)/AKT signaling pathway through Fn1/integrinβ1(ITGB1),leading to the promotion of osteogenesis and the inhibition of adipogenesis.Notably,administration of NELL2-AAV was found to ameliorate bone loss in OVX mice.These findings underscore the significant role of NELL2 in osteoblast differentiation and bone homeostasis,suggesting its potential as a therapeutic target for managing osteoporosis.展开更多
Cognitive dysfunction often occurs in Alzheimer’s disease,Parkinson’s disease,cerebrovascular disease,or other neurodegenerative diseases,and can significantly impact the life quality of patients and create serious ...Cognitive dysfunction often occurs in Alzheimer’s disease,Parkinson’s disease,cerebrovascular disease,or other neurodegenerative diseases,and can significantly impact the life quality of patients and create serious social,psychological,and economic burdens for individuals and their families.Numerous studies have confirmed that exercise can slow the decline in cognitive function through multiple pathways,in which fibronectin type III domain-containing protein 5(FNDC5)plays an important role.However,the current research on the modulation of FNDC5 by exercise and its ability to improve hippocampal cognitive function lacks a systematic and comprehensive understanding.Therefore,this review focuses on the latest research progress regarding the role of exercise-induced FNDC5 in cognitive function,systematically reviews the positive effects of FNDC5 on cognitive function impairment caused by various factors,and clarifies the specific mechanisms by which exerciseinduced FNDC5 improves cognitive function by inhibiting neuroinflammation and improving hippocampal neurogenesis and hippocampal synaptic plasticity.Based on the existing literature,we also identify the areas that require further research in this field.Overall,this review provides a theoretical basis for exercise-based prevention and improvement of cognitive function impairment.展开更多
基金supported by grants from National Natural Science Foundation of China(82272444,81972031,81972033)China Postdoctoral Science Foundation(2022M722382)Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-032A)。
文摘Neural EGFL-like 2(NELL2)is a secreted protein known for its regulatory functions in the nervous and reproductive systems,yet its role in bone biology remains unexplored.In this study,we observed that NELL2 was diminished in the bone of aged and ovariectomized(OVX)mice,as well as in the serum of osteopenia and osteoporosis patients.In vitro loss-of-function and gain-offunction studies revealed that NELL2 facilitated osteoblast differentiation and impeded adipocyte differentiation from stromal progenitor cells.In vivo studies further demonstrated that the deletion of NELL2 in preosteoblasts resulted in decreased cancellous bone mass in mice.Mechanistically,NELL2 interacted with the FNI-type domain located at the C-terminus of Fibronectin 1(Fn1).Moreover,we found that NELL2 activated the focal adhesion kinase(FAK)/AKT signaling pathway through Fn1/integrinβ1(ITGB1),leading to the promotion of osteogenesis and the inhibition of adipogenesis.Notably,administration of NELL2-AAV was found to ameliorate bone loss in OVX mice.These findings underscore the significant role of NELL2 in osteoblast differentiation and bone homeostasis,suggesting its potential as a therapeutic target for managing osteoporosis.
基金supported by the Beijing Natural Science Foundation(No.7222115)the Central University Basic Scientific Research Business Fee Project(No.2023073),China.
文摘Cognitive dysfunction often occurs in Alzheimer’s disease,Parkinson’s disease,cerebrovascular disease,or other neurodegenerative diseases,and can significantly impact the life quality of patients and create serious social,psychological,and economic burdens for individuals and their families.Numerous studies have confirmed that exercise can slow the decline in cognitive function through multiple pathways,in which fibronectin type III domain-containing protein 5(FNDC5)plays an important role.However,the current research on the modulation of FNDC5 by exercise and its ability to improve hippocampal cognitive function lacks a systematic and comprehensive understanding.Therefore,this review focuses on the latest research progress regarding the role of exercise-induced FNDC5 in cognitive function,systematically reviews the positive effects of FNDC5 on cognitive function impairment caused by various factors,and clarifies the specific mechanisms by which exerciseinduced FNDC5 improves cognitive function by inhibiting neuroinflammation and improving hippocampal neurogenesis and hippocampal synaptic plasticity.Based on the existing literature,we also identify the areas that require further research in this field.Overall,this review provides a theoretical basis for exercise-based prevention and improvement of cognitive function impairment.
