Spinal cord injury-induced motor dysfunction is associated with neuroinflammation.Studies have shown that the triterpenoid lupenone,a natural product found in various plants,has a remarkable anti-inflammatory effect i...Spinal cord injury-induced motor dysfunction is associated with neuroinflammation.Studies have shown that the triterpenoid lupenone,a natural product found in various plants,has a remarkable anti-inflammatory effect in the context of chronic inflammation.However,the effects of lupenone on acute inflammation induced by spinal cord injury remain unknown.In this study,we established an impact-induced mouse model of spinal cord injury,and then treated the injured mice with lupenone(8 mg/kg,twice a day)by intrape ritoneal injection.We also treated BV2 cells with lipopolysaccharide and adenosine5’-triphosphate to simulate the inflammatory response after spinal cord injury.Our res ults showed that lupenone reduced IKBa activation and p65 nuclear translocation,inhibited NLRP3 inflammasome function by modulating nuclear factor kappa B,and enhanced the conve rsion of proinflammatory M1 mic roglial cells into anti-inflammatory M2 microglial cells.Furthermore,lupenone decreased NLRP3 inflammasome activation,NLRP3-induced mic roglial cell polarization,and microglia pyroptosis by inhibiting the nuclear factor kappa B pathway.These findings suggest that lupenone protects against spinal cord injury by inhibiting inflammasomes.展开更多
Ossification of the Posterior Longitudinal Ligament(OPLL)is a degenerative hyperostosis disease characterized by the transformation of the soft and elastic vertebral ligament into bone,resulting in limited spinal mobi...Ossification of the Posterior Longitudinal Ligament(OPLL)is a degenerative hyperostosis disease characterized by the transformation of the soft and elastic vertebral ligament into bone,resulting in limited spinal mobility and nerve compression.Employing both bulk and single-cell RNA sequencing,we elucidate the molecular characteristics,cellular components,and their evolution during the OPLL process at a single-cell resolution,and validate these findings in clinical samples.This study also uncovers the capability of ligament stem cells to exhibit endothelial cell-like phenotypes in vitro and in vivo.Notably,our study identifies LOXL2 as a key regulator in this process.Through gain-and loss-of-function studies,we elucidate the role of LOXL2 in the endothelial-like differentiation of ligament cells.It acts via the HIF1A pathway,promoting the secretion of downstream VEGFA and PDGF-BB.This function is not related to the enzymatic activity of LOXL2.Furthermore,we identify sorafenib,a broad-spectrum tyrosine kinase inhibitor,as an effective suppressor of LOXL2-mediated vascular morphogenesis.By disrupting the coupling between vascularization and osteogenesis,sorafenib demonstrates significant inhibition of OPLL progression in both BMP-induced and enpp1 deficiency-induced animal models while having no discernible effect on normal bone mass.These findings underscore the potential of sorafenib as a therapeutic intervention for OPLL.展开更多
Recent studies have determined that the nervous system can sense and respond to signals from skeletal tissue,a process known as skeletal interoception,which is crucial for maintaining bone homeostasis.The hypothalamus...Recent studies have determined that the nervous system can sense and respond to signals from skeletal tissue,a process known as skeletal interoception,which is crucial for maintaining bone homeostasis.The hypothalamus,located in the central nervous system(CNS),plays a key role in processing interoceptive signals and regulating bone homeostasis through the autonomic nervous system,neuropeptide release,and neuroendocrine mechanisms.These mechanisms control the differentiation of mesenchymal stem cells into osteoblasts(OBs),the activation of osteoclasts(OCs),and the functional activities of bone cells.Sensory nerves extensively innervate skeletal tissues,facilitating the transmission of interoceptive signals to the CNS.This review provides a comprehensive overview of current research on the generation and coordination of skeletal interoceptive signals by the CNS to maintain bone homeostasis and their potential role in pathological conditions.The findings expand our understanding of intersystem communication in bone biology and may have implications for developing novel therapeutic strategies for bone diseases.展开更多
基金supported by the National Natural Science Foundation of China,Nos.81801226(to QK and XS)and 82101445(to XJ)。
文摘Spinal cord injury-induced motor dysfunction is associated with neuroinflammation.Studies have shown that the triterpenoid lupenone,a natural product found in various plants,has a remarkable anti-inflammatory effect in the context of chronic inflammation.However,the effects of lupenone on acute inflammation induced by spinal cord injury remain unknown.In this study,we established an impact-induced mouse model of spinal cord injury,and then treated the injured mice with lupenone(8 mg/kg,twice a day)by intrape ritoneal injection.We also treated BV2 cells with lipopolysaccharide and adenosine5’-triphosphate to simulate the inflammatory response after spinal cord injury.Our res ults showed that lupenone reduced IKBa activation and p65 nuclear translocation,inhibited NLRP3 inflammasome function by modulating nuclear factor kappa B,and enhanced the conve rsion of proinflammatory M1 mic roglial cells into anti-inflammatory M2 microglial cells.Furthermore,lupenone decreased NLRP3 inflammasome activation,NLRP3-induced mic roglial cell polarization,and microglia pyroptosis by inhibiting the nuclear factor kappa B pathway.These findings suggest that lupenone protects against spinal cord injury by inhibiting inflammasomes.
基金supported by grants from the National Natural Science Foundation of China(82372431 to L.L.Y.,92168204 and 82225030 to J.L.)the Shanghai Municipal Health Commission(2022LJ007 to L.L.Y.)+3 种基金the Science and Technology Commission of Shanghai Municipality(22ZR1476700 to L.L.Y.)Shanghai Municipal Annual Innovative Medical Device Application Demonstration Project(23SHS05700-06 to L.L.Y.)the Fifth Round Innovation Team of Shanghai Changning District(to L.L.Y.)“Open bidding for selecting the best candidates”cultivation project of Shanghai Changzheng Hospital(2023YJBF-PY10 to L.L.Y.).
文摘Ossification of the Posterior Longitudinal Ligament(OPLL)is a degenerative hyperostosis disease characterized by the transformation of the soft and elastic vertebral ligament into bone,resulting in limited spinal mobility and nerve compression.Employing both bulk and single-cell RNA sequencing,we elucidate the molecular characteristics,cellular components,and their evolution during the OPLL process at a single-cell resolution,and validate these findings in clinical samples.This study also uncovers the capability of ligament stem cells to exhibit endothelial cell-like phenotypes in vitro and in vivo.Notably,our study identifies LOXL2 as a key regulator in this process.Through gain-and loss-of-function studies,we elucidate the role of LOXL2 in the endothelial-like differentiation of ligament cells.It acts via the HIF1A pathway,promoting the secretion of downstream VEGFA and PDGF-BB.This function is not related to the enzymatic activity of LOXL2.Furthermore,we identify sorafenib,a broad-spectrum tyrosine kinase inhibitor,as an effective suppressor of LOXL2-mediated vascular morphogenesis.By disrupting the coupling between vascularization and osteogenesis,sorafenib demonstrates significant inhibition of OPLL progression in both BMP-induced and enpp1 deficiency-induced animal models while having no discernible effect on normal bone mass.These findings underscore the potential of sorafenib as a therapeutic intervention for OPLL.
基金supported by the National Natural Science Foundation of China (No.82172408,81902234,81772314,and 81922045)the Original Exploration project (22ZR1480300)+4 种基金Outstanding Academic Leaders (Youth)project (21XD1422900)of Shanghai Science and Technology Innovation Action PlanPrinciple Investigator Innovation Team of Both Shanghai Sixth People’s Hospital and Shanghai Institute of Nutrition and Health,Shanghai Jiao Tong University Medical College“Two-hundred Talent”Program (No.20191829)The Second Three-Year Action Plan for Promoting Clinical Skills and Clinical Innovation in Municipal Hospitals of Shanghai Shenkang (No.SHDC2020CR4032)Shanghai Excellent Academic Leader ProgramShanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration (No.20DZ2254100)。
文摘Recent studies have determined that the nervous system can sense and respond to signals from skeletal tissue,a process known as skeletal interoception,which is crucial for maintaining bone homeostasis.The hypothalamus,located in the central nervous system(CNS),plays a key role in processing interoceptive signals and regulating bone homeostasis through the autonomic nervous system,neuropeptide release,and neuroendocrine mechanisms.These mechanisms control the differentiation of mesenchymal stem cells into osteoblasts(OBs),the activation of osteoclasts(OCs),and the functional activities of bone cells.Sensory nerves extensively innervate skeletal tissues,facilitating the transmission of interoceptive signals to the CNS.This review provides a comprehensive overview of current research on the generation and coordination of skeletal interoceptive signals by the CNS to maintain bone homeostasis and their potential role in pathological conditions.The findings expand our understanding of intersystem communication in bone biology and may have implications for developing novel therapeutic strategies for bone diseases.
