Increased matrix stiffness of nucleus pulposus(NP)tissue is a main feature of intervertebral disc degeneration(IVDD)and affects various functions of nucleus pulposus cells(NPCs).Glycolysis is the main energy source fo...Increased matrix stiffness of nucleus pulposus(NP)tissue is a main feature of intervertebral disc degeneration(IVDD)and affects various functions of nucleus pulposus cells(NPCs).Glycolysis is the main energy source for NPC survival,but the effects and underlying mechanisms of increased extracellular matrix(ECM)stiffness on NPC glycolysis remain unknown.In this study,hydrogels with different stiffness were established to mimic the mechanical environment of NPCs.Notably,increased matrix stiffness in degenerated NP tissues from IVDD patients was accompanied with impaired glycolysis,and NPCs cultured on rigid substrates exhibited a reduction in glycolysis.展开更多
Intervertebral disc degeneration(IVDD)is the primary contributor to a range of spinal diseases.Dynamin-related protein 1(Drp1)-mediated mitochondrial fission has recently been identified as a new cause of nucleus pulp...Intervertebral disc degeneration(IVDD)is the primary contributor to a range of spinal diseases.Dynamin-related protein 1(Drp1)-mediated mitochondrial fission has recently been identified as a new cause of nucleus pulposus cell(NPC)death and IVDD,but the underlying mechanisms remain unclear.Although the effects of Drp1 phosphorylation in IVDD have been studied,it is currently unknown if small ubiquitin-like modifications(SUMOylation)of Drp1 regulate IVDD.This study aimed to investigate the functions and mechanisms of mitochondria-anchored protein ligase(MAPL),a mitochondrial SUMO E3 ligase,during IVDD progression.The expression of genes related to SUMOylation and mitochondrial dynamics in TNF-α-stimulated NPCs was analysed via RNA sequencing.展开更多
Background:Intervertebral disc degeneration(IVDD)is a multifaceted condition characterized by heterogeneity,wherein the balance between catabolism and anabolism in the extracellular matrix of nucleus pulposus(NP)cells...Background:Intervertebral disc degeneration(IVDD)is a multifaceted condition characterized by heterogeneity,wherein the balance between catabolism and anabolism in the extracellular matrix of nucleus pulposus(NP)cells plays a central role.Presently,the available treatments primarily focus on relieving symptoms associated with IVDD without offering an effective cure targeting its underlying pathophysiological processes.D-mannose(referred to as mannose)has demonstrated anti-catabolic properties in various diseases.Nevertheless,its therapeutic potential in IVDD has yet to be explored.Methods:The study began with optimizing the mannose concentration for restoring NP cells.Transcriptomic analyses were employed to identify the mediators influenced by mannose,with the thioredoxin-interacting protein(TXNIP)gene showing the most significant differences.Subsequently,small interfering RNA(siRNA)technology was used to demonstrate that TXNIP is the key gene through which mannose exerts its effects.Techniques such as colocalization analysis,molecular docking,and overexpression assays further confirmed the direct regulatory relationship between mannose and TXNIP.To elucidate the mechanism of action of mannose,metabolomics techniques were employed to pinpoint glutamine as a core metabolite affected by mannose.Next,various methods,including integrated omics data and the Gene Expression Omnibus(GEO)database,were used to validate the one-way pathway through which TXNIP regulates glutamine.Finally,the therapeutic effect of mannose on IVDD was validated,elucidating the mechanistic role of TXNIP in glutamine metabolism in both intradiscal and orally treated rats.Results:In both in vivo and in vitro experiments,it was discovered that mannose has potent efficacy in alleviating IVDD by inhibiting catabolism.From a mechanistic standpoint,it was shown that mannose exerts its anti-catabolic effects by directly targeting the transcription factor max-like protein X-interacting protein(MondoA),resulting in the upregulation of TXNIP.This upregulation,in turn,inhibits glutamine metabolism,ultimately accomplishing its anticatabolic effects by suppressing the mitogen-activated protein kinase(MAPK)pathway.More importantly,in vivo experiments have further demonstrated that compared with intradiscal injections,oral administration of mannose at safe concentrations can achieve effective therapeutic outcomes.Conclusions:In summary,through integrated multiomics analysis,including both in vivo and in vitro experiments,this study demonstrated that mannose primarily exerts its anti-catabolic effects on IVDD through the TXNIP-glutamine axis.These findings provide strong evidence supporting the potential of the use of mannose in clinical applications for alleviating IVDD.Compared to existing clinically invasive or pain-relieving therapies for IVDD,the oral administration of mannose has characteristics that are more advantageous for clinical IVDD treatment.展开更多
Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment...Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment,but remains a formidable challenge.Here,we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes(Oct4,Klf4 and Sox2)in Cavin2-modified exosomes(OKS@M-Exo)for treatment of IVDD and alleviating LBP.The functional OKS@M-Exo efficaciously alleviated senescence markers(p16^(INK4a),p21^(CIP1)and p53),reduced DNA damage and H4K20me3 expression,as well as restored proliferation ability and metabolic balance in senescent NPCs,as validated through in vitro experiments.In a rat model of IVDD,OKS@M-Exo maintained intervertebral disc height,nucleus pulposus hydration and tissue structure,effectively ameliorated IVDD via decreasing the senescence markers.Additionally,OKS@MExo reduced nociceptive behavior and downregulated nociception markers,indicating its efficiency in alleviating LBP.The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation.Collectively,reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.展开更多
Fibroblast growth factor(FGF)signaling encompasses a multitude of functions,including regulation of cell proliferation,differentiation,morphogenesis,and patterning.FGFs and their receptors(FGFR)are crucial for adult t...Fibroblast growth factor(FGF)signaling encompasses a multitude of functions,including regulation of cell proliferation,differentiation,morphogenesis,and patterning.FGFs and their receptors(FGFR)are crucial for adult tissue repair processes.Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage,bone loss,muscle reduction,and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis(OA),intervertebral disc degeneration(IVDD),osteoporosis(OP),and sarcopenia.In OA and IVDD pathologies specifically,FGF1,FGF2,FGF8,FGF9,FGF18,FGF21,and FGF23 regulate the synthesis,catabolism,and ossification of cartilage tissue.Additionally,the dysregulation of FGFR expression(FGFR1 and FGFR3)promotes the pathological process of cartilage degradation.In OP and sarcopenia,endocrine-derived FGFs(FGF19,FGF21,and FGF23)modulate bone mineral synthesis and decomposition as well as muscle tissues.FGF2 and other FGFs also exert regulatory roles.A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration.Moreover,an increasing number of potential targets within the FGF signaling have been identified,such as FGF9,FGF18,and FGF23.However,it should be noted that most of these discoveries are still in the experimental stage,and further studies are needed before clinical application can be considered.Presently,this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases.Besides,current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated.展开更多
Intervertebral disc degeneration(IVDD)is commonly caused by imbalanced oxygen metabolism-triggered inflammation.Overcoming the shortcomings of antioxidants in IVDD treatment,including instability and the lack of targe...Intervertebral disc degeneration(IVDD)is commonly caused by imbalanced oxygen metabolism-triggered inflammation.Overcoming the shortcomings of antioxidants in IVDD treatment,including instability and the lack of targeting,remains challenging.Microfluidic and surface modification technologies were combined to graft chitosan nanoparticles encapsulated with strong reductive black phosphorus quantum dots(BPQDs)onto GelMA microspheres via amide bonds to construct oxygen metabolism-balanced engineered hydrogel microspheres(GM@CS-BP),which attenuate extracellular acidosis in nucleus pulposus(NP),block the inflammatory cascade,reduce matrix metalloproteinase expression(MMP),and remodel the extracellular matrix(ECM)in intervertebral discs(IVDs).The GM@CS-BP microspheres reduce H_(2)O_(2) intensity by 229%.Chemical grafting and electrostatic attraction increase the encapsulation rate of BPQDs by 167%and maintain stable release for 21 days,demonstrating the antioxidant properties and sustained modulation of the BPQDs.After the GM@CS-BP treatment,western blotting revealed decreased acid-sensitive ion channel-3 and inflammatory factors.Histological staining in an 8-week IVDD model confirmed the regeneration of NP.GM@CS-BP microspheres therefore maintain a balance between ECM synthesis and degradation by regulating the positive feedback between imbalanced oxygen metabolism in IVDs and inflammation.This study provides an in-depth interpretation of the mechanisms underlying the antioxidation of BPQDs and a new approach for IVDD treatment.展开更多
基金supported by the National Nature Science Foundation of China(No.82002345 to J.D and 81902179 to L.S)the Gusu Talent Program(No.Qngg2022008 and GSWS2021027 to J.D)the Preliminary Research Project of the Second Affiliated Hospital of Soochow University(No.SDFEYBS1905 to J.D).
文摘Increased matrix stiffness of nucleus pulposus(NP)tissue is a main feature of intervertebral disc degeneration(IVDD)and affects various functions of nucleus pulposus cells(NPCs).Glycolysis is the main energy source for NPC survival,but the effects and underlying mechanisms of increased extracellular matrix(ECM)stiffness on NPC glycolysis remain unknown.In this study,hydrogels with different stiffness were established to mimic the mechanical environment of NPCs.Notably,increased matrix stiffness in degenerated NP tissues from IVDD patients was accompanied with impaired glycolysis,and NPCs cultured on rigid substrates exhibited a reduction in glycolysis.
基金supported by National Natural Science Foundation of China(82272549,82472505,and 82472498)National key Research and Development plan,Ministry of Science and Technology of the People’s Republic of China(2022YFC2407203)+2 种基金the Young Health Talents of Shanghai Municipal Health Commission,China(2022YQ011)China Medical Education Association(3030537245)The Youth Talent Project of Huashan Hospital(30302164006).
文摘Intervertebral disc degeneration(IVDD)is the primary contributor to a range of spinal diseases.Dynamin-related protein 1(Drp1)-mediated mitochondrial fission has recently been identified as a new cause of nucleus pulposus cell(NPC)death and IVDD,but the underlying mechanisms remain unclear.Although the effects of Drp1 phosphorylation in IVDD have been studied,it is currently unknown if small ubiquitin-like modifications(SUMOylation)of Drp1 regulate IVDD.This study aimed to investigate the functions and mechanisms of mitochondria-anchored protein ligase(MAPL),a mitochondrial SUMO E3 ligase,during IVDD progression.The expression of genes related to SUMOylation and mitochondrial dynamics in TNF-α-stimulated NPCs was analysed via RNA sequencing.
基金supported by the National Key Research and Development Program of China(2020YFB1711505).
文摘Background:Intervertebral disc degeneration(IVDD)is a multifaceted condition characterized by heterogeneity,wherein the balance between catabolism and anabolism in the extracellular matrix of nucleus pulposus(NP)cells plays a central role.Presently,the available treatments primarily focus on relieving symptoms associated with IVDD without offering an effective cure targeting its underlying pathophysiological processes.D-mannose(referred to as mannose)has demonstrated anti-catabolic properties in various diseases.Nevertheless,its therapeutic potential in IVDD has yet to be explored.Methods:The study began with optimizing the mannose concentration for restoring NP cells.Transcriptomic analyses were employed to identify the mediators influenced by mannose,with the thioredoxin-interacting protein(TXNIP)gene showing the most significant differences.Subsequently,small interfering RNA(siRNA)technology was used to demonstrate that TXNIP is the key gene through which mannose exerts its effects.Techniques such as colocalization analysis,molecular docking,and overexpression assays further confirmed the direct regulatory relationship between mannose and TXNIP.To elucidate the mechanism of action of mannose,metabolomics techniques were employed to pinpoint glutamine as a core metabolite affected by mannose.Next,various methods,including integrated omics data and the Gene Expression Omnibus(GEO)database,were used to validate the one-way pathway through which TXNIP regulates glutamine.Finally,the therapeutic effect of mannose on IVDD was validated,elucidating the mechanistic role of TXNIP in glutamine metabolism in both intradiscal and orally treated rats.Results:In both in vivo and in vitro experiments,it was discovered that mannose has potent efficacy in alleviating IVDD by inhibiting catabolism.From a mechanistic standpoint,it was shown that mannose exerts its anti-catabolic effects by directly targeting the transcription factor max-like protein X-interacting protein(MondoA),resulting in the upregulation of TXNIP.This upregulation,in turn,inhibits glutamine metabolism,ultimately accomplishing its anticatabolic effects by suppressing the mitogen-activated protein kinase(MAPK)pathway.More importantly,in vivo experiments have further demonstrated that compared with intradiscal injections,oral administration of mannose at safe concentrations can achieve effective therapeutic outcomes.Conclusions:In summary,through integrated multiomics analysis,including both in vivo and in vitro experiments,this study demonstrated that mannose primarily exerts its anti-catabolic effects on IVDD through the TXNIP-glutamine axis.These findings provide strong evidence supporting the potential of the use of mannose in clinical applications for alleviating IVDD.Compared to existing clinically invasive or pain-relieving therapies for IVDD,the oral administration of mannose has characteristics that are more advantageous for clinical IVDD treatment.
基金supported by the Ministry of Science and Technology of China(2020YFA0908900)National Natural Science Foundation of China(21935011 and 82072490)+1 种基金Shenzhen Science and Technology Innovation Commission(KQTD20200820113012029 and KJZD20230923114612025)Guangdong Provincial Key Laboratory of Advanced Biomaterials(2022B1212010003).
文摘Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment,but remains a formidable challenge.Here,we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes(Oct4,Klf4 and Sox2)in Cavin2-modified exosomes(OKS@M-Exo)for treatment of IVDD and alleviating LBP.The functional OKS@M-Exo efficaciously alleviated senescence markers(p16^(INK4a),p21^(CIP1)and p53),reduced DNA damage and H4K20me3 expression,as well as restored proliferation ability and metabolic balance in senescent NPCs,as validated through in vitro experiments.In a rat model of IVDD,OKS@M-Exo maintained intervertebral disc height,nucleus pulposus hydration and tissue structure,effectively ameliorated IVDD via decreasing the senescence markers.Additionally,OKS@MExo reduced nociceptive behavior and downregulated nociception markers,indicating its efficiency in alleviating LBP.The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation.Collectively,reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.
基金supported by the National Key R&D Program of China(2023YFC3603400)the National Natural Science Foundation of China(82072506,92268115)+2 种基金the Hunan Provincial Science Fund for Distinguished Young Scholars(2024JJ2089)the Science and Technology Innovation Program of Hunan Province(2021RC3025)the National Clinical Research Center for Geriatric Disorders(Xiangya Hospital,2021KF02).
文摘Fibroblast growth factor(FGF)signaling encompasses a multitude of functions,including regulation of cell proliferation,differentiation,morphogenesis,and patterning.FGFs and their receptors(FGFR)are crucial for adult tissue repair processes.Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage,bone loss,muscle reduction,and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis(OA),intervertebral disc degeneration(IVDD),osteoporosis(OP),and sarcopenia.In OA and IVDD pathologies specifically,FGF1,FGF2,FGF8,FGF9,FGF18,FGF21,and FGF23 regulate the synthesis,catabolism,and ossification of cartilage tissue.Additionally,the dysregulation of FGFR expression(FGFR1 and FGFR3)promotes the pathological process of cartilage degradation.In OP and sarcopenia,endocrine-derived FGFs(FGF19,FGF21,and FGF23)modulate bone mineral synthesis and decomposition as well as muscle tissues.FGF2 and other FGFs also exert regulatory roles.A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration.Moreover,an increasing number of potential targets within the FGF signaling have been identified,such as FGF9,FGF18,and FGF23.However,it should be noted that most of these discoveries are still in the experimental stage,and further studies are needed before clinical application can be considered.Presently,this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases.Besides,current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated.
基金supported by the National Natural Science Foundation of China(81972078,82120108017,82072438,82102589,81702190)Social Development Project of Jiangsu Province(BE2021646),Standardized Diagnosis and Treatment Project of Key Diseases in Jiangsu Province(BE2015641)+3 种基金the Natural Science Foundation of Jiangsu Province(BK20211504 and BK20170370)Suzhou Gusu Health Talent Program(GSWS2020001 and GSWS2021007)Jiangsu Innovative and Entrepreneurial Talent Program(JSSCBS20211570)Medical Health Science and Technology Innovation Program of Suzhou(SKY2022119).
文摘Intervertebral disc degeneration(IVDD)is commonly caused by imbalanced oxygen metabolism-triggered inflammation.Overcoming the shortcomings of antioxidants in IVDD treatment,including instability and the lack of targeting,remains challenging.Microfluidic and surface modification technologies were combined to graft chitosan nanoparticles encapsulated with strong reductive black phosphorus quantum dots(BPQDs)onto GelMA microspheres via amide bonds to construct oxygen metabolism-balanced engineered hydrogel microspheres(GM@CS-BP),which attenuate extracellular acidosis in nucleus pulposus(NP),block the inflammatory cascade,reduce matrix metalloproteinase expression(MMP),and remodel the extracellular matrix(ECM)in intervertebral discs(IVDs).The GM@CS-BP microspheres reduce H_(2)O_(2) intensity by 229%.Chemical grafting and electrostatic attraction increase the encapsulation rate of BPQDs by 167%and maintain stable release for 21 days,demonstrating the antioxidant properties and sustained modulation of the BPQDs.After the GM@CS-BP treatment,western blotting revealed decreased acid-sensitive ion channel-3 and inflammatory factors.Histological staining in an 8-week IVDD model confirmed the regeneration of NP.GM@CS-BP microspheres therefore maintain a balance between ECM synthesis and degradation by regulating the positive feedback between imbalanced oxygen metabolism in IVDs and inflammation.This study provides an in-depth interpretation of the mechanisms underlying the antioxidation of BPQDs and a new approach for IVDD treatment.
