The divalent metal cations promote new bone formation through modulation of sensory and sympathetic nervous systems(SNS)activities.In addition,acetylcholine(Ach),as a chief neurotransmitter released by the parasympath...The divalent metal cations promote new bone formation through modulation of sensory and sympathetic nervous systems(SNS)activities.In addition,acetylcholine(Ach),as a chief neurotransmitter released by the parasympathetic nervous system(PNS),also affects bone remodeling,so it is of worth to investigate if the divalent cations influence PNS activity.Of note,these cations are key co-enzymes modulating glucose metabolism.Aerobic glycolysis rather than oxidative phosphorylation favors osteogenesis of mesenchymal stem cells(MSCs),so it is of interest to study the effects of these cations on glucose metabolic pathway.Prior to biological function assessment,the tolerance limits of the divalent metal cations(Mg^(2+),Zn^(2+),and Ca^(2+))and their combinations were profiled.In terms of direct effects,these divalent cations potentially enhanced migration and adhesion capability of MSCs through upregulating Tgf-β1 and Integrin-β1 levels.Interestingly,the divalent cations alone did not influence osteogenesis and aerobic glycolysis of undifferentiated MSCs.However,once the osteogenic differentiation of MSCs was initiated by neurotransmitters or osteogenic differentiation medium,the osteogenesis of MSCs could be significantly promoted by the divalent cations,which was accompanied by the improved aerobic glycolysis.In terms of indirect effects,the divalent cations significantly upregulated levels of sensory nerve derived CGRP,PNS produced choline acetyltransferase and type H vessels,while significantly tuned down sympathetic activity in the defect zone in rats,thereby contributing to significantly increased bone formation relative to the control group.Together,the divalent cations favor bone regeneration via modulation of sensory-autonomic nervous systems and promotion of aerobic glycolysis-driven osteogenesis of MSCs after osteogenic initiation by neurotransmitters.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.:32271381,32471378 and 81971760)the Science and Technology Innovation Commission of Shenzhen(Grant No.:JCYJ20220530145601004)+4 种基金Guangdong Basic and Applied Basic Research Foundation(Grant No.:2024A1515010311)Dalian Medical Science Research Project(Grant NO.:2111038)State Key R&D Program(Grant NO.:2020JH2/10300093)Liaoning Provincial Department of Education Key Research Project(Grant NO.:LJKZZ20220148)Liaoning Provincial Health Commission,"Xingliao Plan of Excellence"Medical Masters Program(Grant NO.:YXMJ-QN-21).
文摘The divalent metal cations promote new bone formation through modulation of sensory and sympathetic nervous systems(SNS)activities.In addition,acetylcholine(Ach),as a chief neurotransmitter released by the parasympathetic nervous system(PNS),also affects bone remodeling,so it is of worth to investigate if the divalent cations influence PNS activity.Of note,these cations are key co-enzymes modulating glucose metabolism.Aerobic glycolysis rather than oxidative phosphorylation favors osteogenesis of mesenchymal stem cells(MSCs),so it is of interest to study the effects of these cations on glucose metabolic pathway.Prior to biological function assessment,the tolerance limits of the divalent metal cations(Mg^(2+),Zn^(2+),and Ca^(2+))and their combinations were profiled.In terms of direct effects,these divalent cations potentially enhanced migration and adhesion capability of MSCs through upregulating Tgf-β1 and Integrin-β1 levels.Interestingly,the divalent cations alone did not influence osteogenesis and aerobic glycolysis of undifferentiated MSCs.However,once the osteogenic differentiation of MSCs was initiated by neurotransmitters or osteogenic differentiation medium,the osteogenesis of MSCs could be significantly promoted by the divalent cations,which was accompanied by the improved aerobic glycolysis.In terms of indirect effects,the divalent cations significantly upregulated levels of sensory nerve derived CGRP,PNS produced choline acetyltransferase and type H vessels,while significantly tuned down sympathetic activity in the defect zone in rats,thereby contributing to significantly increased bone formation relative to the control group.Together,the divalent cations favor bone regeneration via modulation of sensory-autonomic nervous systems and promotion of aerobic glycolysis-driven osteogenesis of MSCs after osteogenic initiation by neurotransmitters.
