MicroRNAs(miRNAs),a class of endogenous single-stranded short noncoding RNAs,have emerged as vital epigenetic regulators of both pathological and physiological processes in animals.They direct fundamental cellular pat...MicroRNAs(miRNAs),a class of endogenous single-stranded short noncoding RNAs,have emerged as vital epigenetic regulators of both pathological and physiological processes in animals.They direct fundamental cellular pathways and processes by fine-tuning the expression of multiple genes at the posttranscriptional level.Growing evidence suggests that mi RNAs are implicated in the onset and development of rheumatoid arthritis(RA).RA is a chronic inflammatory disease that mainly affects synovial joints.This common autoimmune disorder is characterized by a complex and multifaceted pathogenesis,and its morbidity,disability and mortality rates remain consistently high.More in-depth insights into the underlying mechanisms of RA are required to address unmet clinical needs and optimize treatment.Herein,we comprehensively review the deregulated mi RNAs and impaired cellular functions in RA to shed light on several aspects of RA pathogenesis,with a focus on excessive inflammation,synovial hyperplasia and progressive joint damage.This review also provides promising targets for innovative therapies of RA.In addition,we discuss the regulatory roles and clinical potential of extracellular mi RNAs in RA,highlighting their prospective applications as diagnostic and predictive biomarkers.展开更多
Bone mesenchymal stem cells(BMSCs)are stem cells located in the bone marrow matrix that have a variety of differentiation potentials and biological functions.They play an important role in bone regenerative medicine.T...Bone mesenchymal stem cells(BMSCs)are stem cells located in the bone marrow matrix that have a variety of differentiation potentials and biological functions.They play an important role in bone regenerative medicine.The senescence of BMsCs might cause accelerated degeneration of bone tissue.Autophagy is a process in which cellular homeostasis is maintained by autophagosomes and lysosomes.It could control the function and senescence of BMSCs during bone aging and might be a therapeutic target for treating diseases during aging.1 Ferroptosis is a regulated cell death process.2 The inhibition of ferroptosis in mesenchymal stem cells could reduce cell injury and might have great therapeutic value.3-5.展开更多
Osteoarthritis(OA)is a chronic progressive osteoarthropathy in the elderly.Osteoclast activation plays a crucial role in the occurrence of subchondral bone loss in early OA.However,the specific mechanism of osteoclast...Osteoarthritis(OA)is a chronic progressive osteoarthropathy in the elderly.Osteoclast activation plays a crucial role in the occurrence of subchondral bone loss in early OA.However,the specific mechanism of osteoclast differentiation in OA remains unclear.In our study,gene expression profiles related to OA disease progression and osteoclast activation were screened from the Gene Expression Omnibus(GEO)repository.GEO2R and Funrich analysis tools were employed to find differentially expressed genes(DEGs).Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses demonstrated that chemical carcinogenesis,reactive oxygen species(ROS),and response to oxidative stress were mainly involved in osteoclast differentiation in OA subchondral bone.Furthermore,fourteen DEGs that are associated with oxidative stress were identified.The first ranked differential gene,heme oxygenase 1(HMOX1),was selected for further validation.Related results showed that osteoclast activation in the pathogenesis of OA subchondral bone is accompanied by the downregulation of HMOX1.Carnosol was revealed to inhibit osteoclastogenesis by targeting HMOX1 and upregulating the expression of antioxidant protein in vitro.Meanwhile,carnosol was found to alleviate the severity of OA by inhibiting the activation of subchondral osteoclasts in vivo.Our research indicated that the activation of osteoclasts due to subchondral bone redox dysplasia may serve as a significant pathway for the advancement of OA.Targeting HMOX1 in subchondral osteoclasts may offer novel insights for the treatment of early OA.展开更多
Osteoporosis(OP)is a systemic metabolic bone disease characterized by low bone mass,damage to bone microstructure and increased bone fragility.The imbalance of functional coupling between osteoblasts and osteoclasts c...Osteoporosis(OP)is a systemic metabolic bone disease characterized by low bone mass,damage to bone microstructure and increased bone fragility.The imbalance of functional coupling between osteoblasts and osteoclasts contributes to the pathological progression of the disease(Rachner et al.,2011).The pathogenesis of OP is precisely controlled by the complex regulatory network of the bone microenvironment.Metallic elements,although present in small amounts in the body,are essential for their influence on the physiological activities of cells.Metal ions act as effective catalysts and have applications in all stages of cell biochemical evolution(Qian et al.,2021).Bone tissue contains various metal elements,and metal ions play indispensable roles in bone metabolism at the molecular and cellular levels(Luo et al.,2023).However,it is important to note that these metal ions can also contribute to the progression of OP by influencing multiple cellular pathways either directly or indirectly.展开更多
Rheumatoid arthritis(RA)is a chronic inflammatory disease that eventually leads to disability.Inflammatory cell infiltration,severe joint breaking and systemic bone loss are the main clinical symptoms.In this study,we...Rheumatoid arthritis(RA)is a chronic inflammatory disease that eventually leads to disability.Inflammatory cell infiltration,severe joint breaking and systemic bone loss are the main clinical symptoms.In this study,we established a collagen-induced arthritis(CIA)model and found a large number of M1 macrophages and pyroptosis,which are important sources of proinflammatory cytokines.Punicalagin(PUN)is an active substance extracted from pomegranate peel.We found that it inhibited joint inflammation,cartilage damage and systemic bone destruction in CIA mice.PUN effectively alleviated the high expression of inflammatory cytokines in synovial tissue in vivo.PUN treatment shifted macrophages from the M1 phenotype to the M2 phenotype after stimulation with lipopolysaccharide(LPS)and interferon(IFN)-γ.The expression of inducible nitric oxide synthase(i NOS)and other proinflammatory cytokines released by M1 macrophages was decreased in the PUN treatment group.However,simultaneously,the expression of markers of anti-inflammatory M2 macrophages,such as arginase(Arg)-1 and interleukin(IL)-10,was increased.In addition,PUN treatment attenuated pyroptosis by downregulating the expression of NLRP3 and caspase-1,thereby preventing inflammatory cell death resulting from the release of IL-1βand IL-18.Mechanistically,PUN inhibited the activation of receptor activators of the nuclear factor-κB(NF-κB)signaling pathway,which contributes to M1 polarization and pyroptosis of macrophages.We concluded that PUN ameliorated pathological inflammation by inhibiting M1 phenotype polarization and pyroptosis and has great potential as a therapeutic treatment for human RA.展开更多
Surgery is the final choice for most patients with intervertebral disc degeneration(IDD).Operation-caused trauma will cause inflammation in the intervertebral disc.Serious inflammation will cause tissue defects and in...Surgery is the final choice for most patients with intervertebral disc degeneration(IDD).Operation-caused trauma will cause inflammation in the intervertebral disc.Serious inflammation will cause tissue defects and induce tissue degeneration,IDD recurrence and the occurrence of other diseases.Therefore,we proposed a scheme to treat recurrence after discectomy by inhibiting inflammation with an aspirin(ASP)-loaded hydrogel to restore the mechanical stability of the spine and relieve local inflammation.ASP-liposomes(ASP-Lips)were incorporated into a photocrosslinkable gelatin-methacryloyl(GelMA)via mixing.This material can effectively alleviate inflammation by inhibiting the release of high mobility group box 1(HMGB1)from the nucleus to the cytoplasm.We further assessed the expression of inflammatory cytokines,such as interleukin 6(IL-6)and tumor necrosis factor-α(TNF-α),and degeneration-related factors,such as type II collagen(COL-2),Aggrecan,matrix metallopeptidases-3(MMP-3),MMP-13,a disintegrin and metalloproteinase with thrombospondin motifs-4(ADAMTS-4)and ADAMTS-5 in rat nucleus pulpous cells.The level of IDD was analyzed through H&E,safranin-O staining and immunohistochemistry in rabbit samples.In vitro,we found that ASP-Lip@GelMA treatment significantly decreased inflammatory cytokines,MMP-3 and-13,and ADAMTS-4 and-5 and up-regulated COL-2 and Aggrecan via the inhibited release of HMGB-1 from the nucleus.In vivo,ASP-Lip@GelMA can effectively inhibit inflammation of local tissue after disc surgery and fill local tissue defects.This composite hydrogel system is a promising way to treat the recurrence of IDD after surgery without persistent complications.展开更多
Periprosthetic osteolysis(PPO)remains the key factor in implant failure and subsequent revision surgery and is mainly triggered by wear particles.Previous studies have shown that inhibition of osteoblastic differentia...Periprosthetic osteolysis(PPO)remains the key factor in implant failure and subsequent revision surgery and is mainly triggered by wear particles.Previous studies have shown that inhibition of osteoblastic differentiation is the most widespread incident affecting the interface of trabecular and loosening prostheses.Additionally,the NLRP3 inflammasome is activated by prosthetic particles.Sirtuin3,an NAD+-dependent deacetylase of mitochondria,regulates the function of mitochondria in diverse activities.However,whether SIRT3 can mitigate wear debris-induced osteolysis by inhibiting the NLRP3 inflammasome and enhancing osteogenesis has not been previously reported.Therefore,we investigated the role of SIRT3 during the process of titanium(Ti)particle-induced osteolysis.We revealed that upregulated SIRT3 dramatically attenuated Ti particle-induced osteogenic inhibition through suppression of the NLRP3 inflammasome and improvement of osteogenesis in vivo and in vitro.Moreover,we found that SIRT3 interference in the process of Ti particle-induced osteolysis relied on the GSK-3β/β-catenin signalling pathway.Collectively,these findings indicated that SIRT3 may serve as a rational new treatment against debris-induced PPO by deacetylase-dependent inflammasome attenuation.展开更多
Since the proposal of Paul Ehrlich’s magic bullet concept over 100 years ago,tremendous advances have occurred in targeted therapy.From the initial selective antibody,antitoxin to targeted drug delivery that emerged ...Since the proposal of Paul Ehrlich’s magic bullet concept over 100 years ago,tremendous advances have occurred in targeted therapy.From the initial selective antibody,antitoxin to targeted drug delivery that emerged in the past decades,more precise therapeutic efficacy is realized in specific pathological sites of clinical diseases.As a highly pyknotic mineralized tissue with lessened blood flow,bone is characterized by a complex remodeling and homeostatic regulation mechanism,which makes drug therapy for skeletal diseases more challenging than other tissues.Bone-targeted therapy has been considered a promising therapeutic approach for handling such drawbacks.With the deepening understanding of bone biology,improvements in some established bone-targeted drugs and novel therapeutic targets for drugs and deliveries have emerged on the horizon.In this review,we provide a panoramic summary of recent advances in therapeutic strategies based on bone targeting.We highlight targeting strategies based on bone structure and remodeling biology.For bone-targeted therapeutic agents,in addition to improvements of the classic denosumab,romosozumab,and PTH1R ligands,potential regulation of the remodeling process targeting other key membrane expressions,cellular crosstalk,and gene expression,of all bone cells has been exploited.For bone-targeted drug delivery,different delivery strategies targeting bone matrix,bone marrow,and specific bone cells are summarized with a comparison between different targeting ligands.Ultimately,this review will summarize recent advances in the clinical translation of bone-targeted therapies and provide a perspective on the challenges for the application of bone-targeted therapy in the clinic and future trends in this area.展开更多
Polyetheretherketone(PEEK)is a desirable alternative to conventional biomedical metals for orthopedic implants due to the excellent mechanical properties.However,the inherent bioinertness of PEEK contributes to inferi...Polyetheretherketone(PEEK)is a desirable alternative to conventional biomedical metals for orthopedic implants due to the excellent mechanical properties.However,the inherent bioinertness of PEEK contributes to inferior osseointegration of PEEK implants,especially under pathological conditions of osteoporosis.Herein,a programmed surface is designed and fabricated on PEEK to dictate osteoimmunomodulation and bone regeneration sequentially.A degradable hybrid coating consisting of poly(lactide-co-glycolide)and alendronate(ALN)loaded nano-hydroxyapatite is deposited on PEEK and then interleukin-4(IL-4)is grafted onto the outer surface of the hybrid coating with the aid of N_(2) plasma immersion ion implantation and subsequent immersion in IL-4 solution.Dominant release of IL-4 together with ALN and Ca^(2+) during the first few days synergistically mitigates the early acute inflammatory reactions and creates an osteoimmunomodulatory microenvironment that facilitates bone regeneration.Afterwards,slow and sustained delivery of ALN and Ca^(2+) in the following weeks boosts osteogenesis and suppresses osteoclastogenesis simultaneously,consequently ameliorating bone-implant osseointegration even under osteoporotic conditions.By taking into account the different phases in bone repair,this strategy of constructing advanced bone implants with sequential functions provides customizable and clinically viable therapy to osteoporotic patients.展开更多
Polyetheretherketone(PEEK)has been widely used as orthopedic and dental materials due to excellent mechanical and physicochemical tolerance.However,its biological inertness,poor osteoinduction,and weak antibacterial a...Polyetheretherketone(PEEK)has been widely used as orthopedic and dental materials due to excellent mechanical and physicochemical tolerance.However,its biological inertness,poor osteoinduction,and weak antibacterial activity make the clinical applications in a dilemma.Inspired by the mussel adhesion mechanism,here we reported a biomimetic surface strategy for rational integration and optimization of anti-infectivity and osteo-inductivity onto PEEK surfaces using a mussel foot proteins(Mfps)-mimic peptide with clickable azido terminal.The peptide enables mussel-like adhesion on PEEK biomaterial surfaces,leaving azido groups for the further steps of biofunctionalizations.In this study,antimicrobial peptide(AMP)and osteogenic growth peptide(OGP)were bioorthogonally clicked on the azido-modified PEEK biomaterials to obtain a dual-effect of host defense and tissue repair.Since bioorthogonal clicking allows precise collocation between AMP and OGP through changing their feeding molar ratios,an optimal PEEK surface was finally obtained in this research,which could long-term inhibit bacterial growth,stabilize bone homeostasis and facilitate interfacial bone regeneration.In a word,this upgraded mussel surface strategy proposed in this study is promising for the surface bioengineering of inert medical implants,in particular,achieving rational integration of multiple biofunctions to match clinical requirements.展开更多
Bone-related diseases refer to a group of skeletal disorders that are characterized by bone and cartilage destruction.Conventional approaches can regulate bone homeostasis to a certain extent.However,these therapies a...Bone-related diseases refer to a group of skeletal disorders that are characterized by bone and cartilage destruction.Conventional approaches can regulate bone homeostasis to a certain extent.However,these therapies are still associated with some undesirable problems.Fortunately,recent advances in nanomaterials have provided unprecedented opportunities for diagnosis and therapy of bone-related diseases.This review provides a comprehensive and up-to-date overview of current advanced theranostic nanomaterials in bone-related diseases.First,the potential utility of nanomaterials for biological imaging and biomarker detection is illustrated.Second,nanomaterials serve as therapeutic delivery platforms with special functions for bone homeostasis regulation and cellular modulation are highlighted.Finally,perspectives in this field are offered,including current key bottlenecks and future directions,which may be helpful for exploiting nanomaterials with novel properties and unique functions.This review will provide scientific guidance to enhance the development of advanced nanomaterials for the diagnosis and therapy of bone-related diseases.展开更多
Nanozymes are considered to represent a new era of antibacterial agents,while their antibacterial efficiency is limited by the increasing tissue depth of infection.To address this issue,here,we report a copper and sil...Nanozymes are considered to represent a new era of antibacterial agents,while their antibacterial efficiency is limited by the increasing tissue depth of infection.To address this issue,here,we report a copper and silk fibroin(Cu-SF)complex strategy to synthesize alternative copper single-atom nanozymes(SAzymes)with atomically dispersed copper sites anchored on ultrathin 2D porous N-doped carbon nanosheets(CuN_(x)-CNS)and tunable N coordination numbers in the CuN_(x) sites(x=2 or 4).The CuN_(x)-CNS SAzymes inherently possess triple peroxidase(POD)-,catalase(CAT)-,and oxidase(OXD)-like activities,facilitating the conversion of H_(2)O_(2)and O_(2)into reactive oxygen species(ROS)through parallel POD-and OXD-like or cascaded CAT-and OXD-like reactions.Compared to CuN_(2)-CNS,tailoring the N coordination number from 2 to 4 endows the SAzyme(CuN_(4)-CNS)with higher multienzyme activities due to its superior electron structure and lower energy barrier.Meanwhile,CuN_(x)-CNS display strong absorption in the second near-infrared(NIR-II)biowindow with deeper tissue penetration,offering NIR-II-responsive enhanced ROS generation and photothermal treatment in deep tissues.The in vitro and in vivo results demonstrate that the optimal CuN_(4)-CNS can effectively inhibit multidrug-resistant bacteria and eliminate stubborn biofilms,thus exhibiting high therapeutic efficacy in both superficial skin wound and deep implant-related biofilm infections.展开更多
For patients with osteoporosis,the therapeutic outcomes of osteoimplants are substantially affected by the impaired proliferation,migration,and osteogenic differentiation abilities of bone marrow mesenchymal stem cell...For patients with osteoporosis,the therapeutic outcomes of osteoimplants are substantially affected by the impaired proliferation,migration,and osteogenic differentiation abilities of bone marrow mesenchymal stem cells(BMSCs).展开更多
Skeletal diseases normally represents a grievous imbalance between osteoblasts for bone formation and osteoclasts for bone resorption.A lack of osteogenic function can make it difficult to repair pathological bone ero...Skeletal diseases normally represents a grievous imbalance between osteoblasts for bone formation and osteoclasts for bone resorption.A lack of osteogenic function can make it difficult to repair pathological bone erosion.Therefore,substantial efforts have been made to remedy these issues,with the aid of bioactive molecules,herbs and materials.Following recent insights,the importance of epigenetic gene regulation is increasingly evident,especially microRNAs.MicroRNAs can silence target genes by inhibiting mRNA translation or degrading mRNA molecules by binding to their 3′-untranslated region.There is accumulating evidence indicating that the miRNAs significantly involved in osteogenic gene expression,signaling pathway intervention and programmed cell death.Besides,numerous new target drugs(microRNA inhibitors or agonists)have been proposed to exploit its value in skeletal physiology and pathology.In this review,we mainly discuss the role of microRNAs in the context of skeletal disease-associated osteoblast differentiation,the applications of microRNA polymorphisms as biomarkers for diagnostic and therapeutic targets,and the challenges to meet this goal.Our summary provides novel horizon for improving the therapeutic effect of microRNAs,which may be beneficial to the further clinical translation of microRNAs in the treatments of skeletal diseases.展开更多
基金National Natural Science Foundation of China(82072425,82072498,82272157)Natural Science Foundation of Jiangsu Province(BE2020666,BK2021650)+3 种基金Jiangsu Medical Research Project(ZD2022021)Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)Special Project of Diagnosis and Treatment Technology for Key Clinical Diseases in Suzhou(LCZX202003)Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX22_3217)。
文摘MicroRNAs(miRNAs),a class of endogenous single-stranded short noncoding RNAs,have emerged as vital epigenetic regulators of both pathological and physiological processes in animals.They direct fundamental cellular pathways and processes by fine-tuning the expression of multiple genes at the posttranscriptional level.Growing evidence suggests that mi RNAs are implicated in the onset and development of rheumatoid arthritis(RA).RA is a chronic inflammatory disease that mainly affects synovial joints.This common autoimmune disorder is characterized by a complex and multifaceted pathogenesis,and its morbidity,disability and mortality rates remain consistently high.More in-depth insights into the underlying mechanisms of RA are required to address unmet clinical needs and optimize treatment.Herein,we comprehensively review the deregulated mi RNAs and impaired cellular functions in RA to shed light on several aspects of RA pathogenesis,with a focus on excessive inflammation,synovial hyperplasia and progressive joint damage.This review also provides promising targets for innovative therapies of RA.In addition,we discuss the regulatory roles and clinical potential of extracellular mi RNAs in RA,highlighting their prospective applications as diagnostic and predictive biomarkers.
基金supported by the National Natural Science Foundation of China(No.82072425)the Natural Science Foundation of Jiangsu Province,China(No.BK20220059)the Jiangsu Medical Research Project(China)(No.ZD2022021)。
文摘Bone mesenchymal stem cells(BMSCs)are stem cells located in the bone marrow matrix that have a variety of differentiation potentials and biological functions.They play an important role in bone regenerative medicine.The senescence of BMsCs might cause accelerated degeneration of bone tissue.Autophagy is a process in which cellular homeostasis is maintained by autophagosomes and lysosomes.It could control the function and senescence of BMSCs during bone aging and might be a therapeutic target for treating diseases during aging.1 Ferroptosis is a regulated cell death process.2 The inhibition of ferroptosis in mesenchymal stem cells could reduce cell injury and might have great therapeutic value.3-5.
基金supported by the National Natural Science Foundation of China(Nos.82272157,82072425,and 82072498)the Natural Science Foundation of Jiangsu Province(No.BE2021650)+3 种基金the Priority Academic Program Development(PAPD)of Jiangsu Higher Education Institutions,the Program of Suzhou Health Commission(Nos.GSWS2022002 and GSWS2020121)the Jiangsu Medical Research Project(No.ZD2022014)the National and Local Engineering Laboratory of New Functional Polymer Materials(No.SDGC2205)the Special Project of Diagnosis and Treatment Technology for Key Clinical Diseases in Suzhou(No.LCZX202003),China.
文摘Osteoarthritis(OA)is a chronic progressive osteoarthropathy in the elderly.Osteoclast activation plays a crucial role in the occurrence of subchondral bone loss in early OA.However,the specific mechanism of osteoclast differentiation in OA remains unclear.In our study,gene expression profiles related to OA disease progression and osteoclast activation were screened from the Gene Expression Omnibus(GEO)repository.GEO2R and Funrich analysis tools were employed to find differentially expressed genes(DEGs).Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses demonstrated that chemical carcinogenesis,reactive oxygen species(ROS),and response to oxidative stress were mainly involved in osteoclast differentiation in OA subchondral bone.Furthermore,fourteen DEGs that are associated with oxidative stress were identified.The first ranked differential gene,heme oxygenase 1(HMOX1),was selected for further validation.Related results showed that osteoclast activation in the pathogenesis of OA subchondral bone is accompanied by the downregulation of HMOX1.Carnosol was revealed to inhibit osteoclastogenesis by targeting HMOX1 and upregulating the expression of antioxidant protein in vitro.Meanwhile,carnosol was found to alleviate the severity of OA by inhibiting the activation of subchondral osteoclasts in vivo.Our research indicated that the activation of osteoclasts due to subchondral bone redox dysplasia may serve as a significant pathway for the advancement of OA.Targeting HMOX1 in subchondral osteoclasts may offer novel insights for the treatment of early OA.
基金supported by the National Natural Science Foundation of China(82072425,82072498,82272567)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)and the Program of Jiangsu Science and Technology Department(BE2021637)+3 种基金Jiangsu Medical Research Project(ZD2022014)Special Project of Diagnosis and Treatment Technology for Key Clinical Diseases in Suzhou(LCZX202003)the Program of Suzhou Health Commission(GSWS2022002)National and Local Engineering Laboratory of New Functional Polymer Materials(SDGC2205).
文摘Osteoporosis(OP)is a systemic metabolic bone disease characterized by low bone mass,damage to bone microstructure and increased bone fragility.The imbalance of functional coupling between osteoblasts and osteoclasts contributes to the pathological progression of the disease(Rachner et al.,2011).The pathogenesis of OP is precisely controlled by the complex regulatory network of the bone microenvironment.Metallic elements,although present in small amounts in the body,are essential for their influence on the physiological activities of cells.Metal ions act as effective catalysts and have applications in all stages of cell biochemical evolution(Qian et al.,2021).Bone tissue contains various metal elements,and metal ions play indispensable roles in bone metabolism at the molecular and cellular levels(Luo et al.,2023).However,it is important to note that these metal ions can also contribute to the progression of OP by influencing multiple cellular pathways either directly or indirectly.
基金supported by the National Natural Science Foundation of China(82072425,82072498,81902181,81873990,81873991,and 81672238)the Jiangsu Provincial Medical Youth Talent(QNRC2016751)+4 种基金the Natural Science Foundation of Jiangsu Province(BK20180001)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)the Special Project of Diagnosis and Treatment Technology for Key Clinical Diseases in Suzhou(LCZX202003)the Program for Introduction of Clinical Medical Teams to Suzhou(SZYJTD201714)Program from Suzhou Science and Technology Bureau(SYS2019101)。
文摘Rheumatoid arthritis(RA)is a chronic inflammatory disease that eventually leads to disability.Inflammatory cell infiltration,severe joint breaking and systemic bone loss are the main clinical symptoms.In this study,we established a collagen-induced arthritis(CIA)model and found a large number of M1 macrophages and pyroptosis,which are important sources of proinflammatory cytokines.Punicalagin(PUN)is an active substance extracted from pomegranate peel.We found that it inhibited joint inflammation,cartilage damage and systemic bone destruction in CIA mice.PUN effectively alleviated the high expression of inflammatory cytokines in synovial tissue in vivo.PUN treatment shifted macrophages from the M1 phenotype to the M2 phenotype after stimulation with lipopolysaccharide(LPS)and interferon(IFN)-γ.The expression of inducible nitric oxide synthase(i NOS)and other proinflammatory cytokines released by M1 macrophages was decreased in the PUN treatment group.However,simultaneously,the expression of markers of anti-inflammatory M2 macrophages,such as arginase(Arg)-1 and interleukin(IL)-10,was increased.In addition,PUN treatment attenuated pyroptosis by downregulating the expression of NLRP3 and caspase-1,thereby preventing inflammatory cell death resulting from the release of IL-1βand IL-18.Mechanistically,PUN inhibited the activation of receptor activators of the nuclear factor-κB(NF-κB)signaling pathway,which contributes to M1 polarization and pyroptosis of macrophages.We concluded that PUN ameliorated pathological inflammation by inhibiting M1 phenotype polarization and pyroptosis and has great potential as a therapeutic treatment for human RA.
基金support of the following funds for our study:National Nature Science Foundation of China(81873991 and 81972104)Natural Science Foundation of Jiangsu Province(BK20180001)+1 种基金a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)Application of Key Technology Research Program of Suzhou City(SS201858).
文摘Surgery is the final choice for most patients with intervertebral disc degeneration(IDD).Operation-caused trauma will cause inflammation in the intervertebral disc.Serious inflammation will cause tissue defects and induce tissue degeneration,IDD recurrence and the occurrence of other diseases.Therefore,we proposed a scheme to treat recurrence after discectomy by inhibiting inflammation with an aspirin(ASP)-loaded hydrogel to restore the mechanical stability of the spine and relieve local inflammation.ASP-liposomes(ASP-Lips)were incorporated into a photocrosslinkable gelatin-methacryloyl(GelMA)via mixing.This material can effectively alleviate inflammation by inhibiting the release of high mobility group box 1(HMGB1)from the nucleus to the cytoplasm.We further assessed the expression of inflammatory cytokines,such as interleukin 6(IL-6)and tumor necrosis factor-α(TNF-α),and degeneration-related factors,such as type II collagen(COL-2),Aggrecan,matrix metallopeptidases-3(MMP-3),MMP-13,a disintegrin and metalloproteinase with thrombospondin motifs-4(ADAMTS-4)and ADAMTS-5 in rat nucleus pulpous cells.The level of IDD was analyzed through H&E,safranin-O staining and immunohistochemistry in rabbit samples.In vitro,we found that ASP-Lip@GelMA treatment significantly decreased inflammatory cytokines,MMP-3 and-13,and ADAMTS-4 and-5 and up-regulated COL-2 and Aggrecan via the inhibited release of HMGB-1 from the nucleus.In vivo,ASP-Lip@GelMA can effectively inhibit inflammation of local tissue after disc surgery and fill local tissue defects.This composite hydrogel system is a promising way to treat the recurrence of IDD after surgery without persistent complications.
基金This work is supported by grants from the National Natural Science Foundation of China(Nos.82072425,82072498,81873991,81873990,81672238 and 81472077)the Young Medical Talents of Jiangsu Province(No.QNRC2016751)+1 种基金the Natural Science Foundation of Jiangsu Province(Nos.BK20180001)the Priority Academic Program Development of Jiangsu Higher Education Institutions and Special Project of Diagnosis and Treatment Technology for Key Clinical Diseases in Suzhou(LCZX202003).
文摘Periprosthetic osteolysis(PPO)remains the key factor in implant failure and subsequent revision surgery and is mainly triggered by wear particles.Previous studies have shown that inhibition of osteoblastic differentiation is the most widespread incident affecting the interface of trabecular and loosening prostheses.Additionally,the NLRP3 inflammasome is activated by prosthetic particles.Sirtuin3,an NAD+-dependent deacetylase of mitochondria,regulates the function of mitochondria in diverse activities.However,whether SIRT3 can mitigate wear debris-induced osteolysis by inhibiting the NLRP3 inflammasome and enhancing osteogenesis has not been previously reported.Therefore,we investigated the role of SIRT3 during the process of titanium(Ti)particle-induced osteolysis.We revealed that upregulated SIRT3 dramatically attenuated Ti particle-induced osteogenic inhibition through suppression of the NLRP3 inflammasome and improvement of osteogenesis in vivo and in vitro.Moreover,we found that SIRT3 interference in the process of Ti particle-induced osteolysis relied on the GSK-3β/β-catenin signalling pathway.Collectively,these findings indicated that SIRT3 may serve as a rational new treatment against debris-induced PPO by deacetylase-dependent inflammasome attenuation.
基金supported by the National Natural Science Foundation of China(82072425,82072498,82272157)the Natural Science Foundation of Jiangsu Province(BK2021650)+5 种基金the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)Jiangsu Medical Research Project(ZD2022021)Special Project of DiagnosisTreatment Technology for Key Clinical Diseases in Suzhou(LCZX202003)Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX22_3217)the Program of Suzhou Health Commission(GSWS2022002).
文摘Since the proposal of Paul Ehrlich’s magic bullet concept over 100 years ago,tremendous advances have occurred in targeted therapy.From the initial selective antibody,antitoxin to targeted drug delivery that emerged in the past decades,more precise therapeutic efficacy is realized in specific pathological sites of clinical diseases.As a highly pyknotic mineralized tissue with lessened blood flow,bone is characterized by a complex remodeling and homeostatic regulation mechanism,which makes drug therapy for skeletal diseases more challenging than other tissues.Bone-targeted therapy has been considered a promising therapeutic approach for handling such drawbacks.With the deepening understanding of bone biology,improvements in some established bone-targeted drugs and novel therapeutic targets for drugs and deliveries have emerged on the horizon.In this review,we provide a panoramic summary of recent advances in therapeutic strategies based on bone targeting.We highlight targeting strategies based on bone structure and remodeling biology.For bone-targeted therapeutic agents,in addition to improvements of the classic denosumab,romosozumab,and PTH1R ligands,potential regulation of the remodeling process targeting other key membrane expressions,cellular crosstalk,and gene expression,of all bone cells has been exploited.For bone-targeted drug delivery,different delivery strategies targeting bone matrix,bone marrow,and specific bone cells are summarized with a comparison between different targeting ligands.Ultimately,this review will summarize recent advances in the clinical translation of bone-targeted therapies and provide a perspective on the challenges for the application of bone-targeted therapy in the clinic and future trends in this area.
基金financial support from the National Natural Science Foundation of China(Nos.31922040 and 82001965)Shenzhen Science and Technology Research Funding(Nos.SGLH20180625144002074,JCYJ20180507182637685,and JCYJ20190806165616542)+5 种基金Youth Innovation Promotion Association of Chinese Academy of Sciences(Nos.2017416 and 2020353)Guangdong Basic and Applied Basic Research Foundation(No.2020B1515120078)China Postdoctoral Science Foundation(2019M663190)SIAT Innovation Program for Excellent Young Researchers(E1G034)Nanchong Science and Technology Project(No.20SXQT0302)City University of Hong Kong Strategic Research Grant(SRG)(No.7005505).
文摘Polyetheretherketone(PEEK)is a desirable alternative to conventional biomedical metals for orthopedic implants due to the excellent mechanical properties.However,the inherent bioinertness of PEEK contributes to inferior osseointegration of PEEK implants,especially under pathological conditions of osteoporosis.Herein,a programmed surface is designed and fabricated on PEEK to dictate osteoimmunomodulation and bone regeneration sequentially.A degradable hybrid coating consisting of poly(lactide-co-glycolide)and alendronate(ALN)loaded nano-hydroxyapatite is deposited on PEEK and then interleukin-4(IL-4)is grafted onto the outer surface of the hybrid coating with the aid of N_(2) plasma immersion ion implantation and subsequent immersion in IL-4 solution.Dominant release of IL-4 together with ALN and Ca^(2+) during the first few days synergistically mitigates the early acute inflammatory reactions and creates an osteoimmunomodulatory microenvironment that facilitates bone regeneration.Afterwards,slow and sustained delivery of ALN and Ca^(2+) in the following weeks boosts osteogenesis and suppresses osteoclastogenesis simultaneously,consequently ameliorating bone-implant osseointegration even under osteoporotic conditions.By taking into account the different phases in bone repair,this strategy of constructing advanced bone implants with sequential functions provides customizable and clinically viable therapy to osteoporotic patients.
基金supported by the National Key Research and Development Program of China(2019YFA0112000)Research and Development of Biomedical Materials and Substitution of Tissue and Organ Repair under the National Key R&D Program(2016YFC1101505)+7 种基金the National Natural Science Foundation of China(82072425,82072498,81873991,81073990,21875092,31922040 and 81672238)the Young Medical Talents of Jiangsu Province(QNRC2016751)the Natural Science Foundation of Jiangsu Province(BK20180001)the Innovation and Entrepreneurship Program of Jiangsu Provincethe“Six Talent Peaks”program of Jiangsu Province(2018-XCL-013)the Basic Applied Research Program of Suzhou City(SYS2018032,KJXW2017009)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)the Special Project of Diagnosis and Treatment for Clinical Diseases of Suzhou(LCZX202003).
文摘Polyetheretherketone(PEEK)has been widely used as orthopedic and dental materials due to excellent mechanical and physicochemical tolerance.However,its biological inertness,poor osteoinduction,and weak antibacterial activity make the clinical applications in a dilemma.Inspired by the mussel adhesion mechanism,here we reported a biomimetic surface strategy for rational integration and optimization of anti-infectivity and osteo-inductivity onto PEEK surfaces using a mussel foot proteins(Mfps)-mimic peptide with clickable azido terminal.The peptide enables mussel-like adhesion on PEEK biomaterial surfaces,leaving azido groups for the further steps of biofunctionalizations.In this study,antimicrobial peptide(AMP)and osteogenic growth peptide(OGP)were bioorthogonally clicked on the azido-modified PEEK biomaterials to obtain a dual-effect of host defense and tissue repair.Since bioorthogonal clicking allows precise collocation between AMP and OGP through changing their feeding molar ratios,an optimal PEEK surface was finally obtained in this research,which could long-term inhibit bacterial growth,stabilize bone homeostasis and facilitate interfacial bone regeneration.In a word,this upgraded mussel surface strategy proposed in this study is promising for the surface bioengineering of inert medical implants,in particular,achieving rational integration of multiple biofunctions to match clinical requirements.
基金supported by the National Natural Science Foundation of China(82072425,82072498,81871788,21875092,31922040,82272157)the Natural Science Foundation of Jiangsu Province(BK2021650 and BK20220059)+5 种基金the“Jiangsu Specially-Appointed Professor”Programthe Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)Jiangsu Medical Research Project(ZD2022021)Special Project of DiagnosisTreatment Technology for Key Clinical Diseases in Suzhou(LCZX202003)Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX22_3217).
文摘Bone-related diseases refer to a group of skeletal disorders that are characterized by bone and cartilage destruction.Conventional approaches can regulate bone homeostasis to a certain extent.However,these therapies are still associated with some undesirable problems.Fortunately,recent advances in nanomaterials have provided unprecedented opportunities for diagnosis and therapy of bone-related diseases.This review provides a comprehensive and up-to-date overview of current advanced theranostic nanomaterials in bone-related diseases.First,the potential utility of nanomaterials for biological imaging and biomarker detection is illustrated.Second,nanomaterials serve as therapeutic delivery platforms with special functions for bone homeostasis regulation and cellular modulation are highlighted.Finally,perspectives in this field are offered,including current key bottlenecks and future directions,which may be helpful for exploiting nanomaterials with novel properties and unique functions.This review will provide scientific guidance to enhance the development of advanced nanomaterials for the diagnosis and therapy of bone-related diseases.
基金the National Natural Science Foundation of China(32222041,82072425,82160421,and 82072498)the Natural Science Foundation of Jiangsu Province(BE2020666,BK20211322,and BK20220059)+3 种基金Finland-China Food and Health International Pilot Project funded by the Finnish Ministry of Education and Culture,the Academy Research Fellow(328933)Solutions for Health Strategic Research Profiling Area(336355)InFLAMES Flagship(337531)Grants from Academy of Finland,the Special Project of Diagnosis and Treatment for Clinical Diseases of Suzhou(LCZX202003)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD),and the jiangsu Specially Appointed Professor"Program and Postgraduate Research&Practice Innovation Program of jiangsu Province(KYCX22_3217).
文摘Nanozymes are considered to represent a new era of antibacterial agents,while their antibacterial efficiency is limited by the increasing tissue depth of infection.To address this issue,here,we report a copper and silk fibroin(Cu-SF)complex strategy to synthesize alternative copper single-atom nanozymes(SAzymes)with atomically dispersed copper sites anchored on ultrathin 2D porous N-doped carbon nanosheets(CuN_(x)-CNS)and tunable N coordination numbers in the CuN_(x) sites(x=2 or 4).The CuN_(x)-CNS SAzymes inherently possess triple peroxidase(POD)-,catalase(CAT)-,and oxidase(OXD)-like activities,facilitating the conversion of H_(2)O_(2)and O_(2)into reactive oxygen species(ROS)through parallel POD-and OXD-like or cascaded CAT-and OXD-like reactions.Compared to CuN_(2)-CNS,tailoring the N coordination number from 2 to 4 endows the SAzyme(CuN_(4)-CNS)with higher multienzyme activities due to its superior electron structure and lower energy barrier.Meanwhile,CuN_(x)-CNS display strong absorption in the second near-infrared(NIR-II)biowindow with deeper tissue penetration,offering NIR-II-responsive enhanced ROS generation and photothermal treatment in deep tissues.The in vitro and in vivo results demonstrate that the optimal CuN_(4)-CNS can effectively inhibit multidrug-resistant bacteria and eliminate stubborn biofilms,thus exhibiting high therapeutic efficacy in both superficial skin wound and deep implant-related biofilm infections.
基金This review work was supported by the National Natural Science Foundation of China(32222041,82072425,82072498,and 21875092)the Natural Science Foundation of Jiangsu Province(BK20220059 and BE2020666)+2 种基金the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)the Special Project of Diagnosis and Treatment Technology for Key Clinical Diseases in Suzhou(LCZX202003)the“jiangsu Specially Appointed Professor”Program and Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX22_3217).
文摘For patients with osteoporosis,the therapeutic outcomes of osteoimplants are substantially affected by the impaired proliferation,migration,and osteogenic differentiation abilities of bone marrow mesenchymal stem cells(BMSCs).
基金supported by grants from the National Natural Sci-ence Foundation of China(82072425,82072498,82074473,81873991,31922040 and 81873990)the Young Medical Talents of Jiangsu Province(QNRC2016751)+1 种基金the Natural Science Foundation of Jiangsu Province(BK20200198,BE2021650)Special Project of Diagno-sis and Treatment Technology for Key Clinical Diseases in Suzhou(LCZX202003,LCZX201824).
文摘Skeletal diseases normally represents a grievous imbalance between osteoblasts for bone formation and osteoclasts for bone resorption.A lack of osteogenic function can make it difficult to repair pathological bone erosion.Therefore,substantial efforts have been made to remedy these issues,with the aid of bioactive molecules,herbs and materials.Following recent insights,the importance of epigenetic gene regulation is increasingly evident,especially microRNAs.MicroRNAs can silence target genes by inhibiting mRNA translation or degrading mRNA molecules by binding to their 3′-untranslated region.There is accumulating evidence indicating that the miRNAs significantly involved in osteogenic gene expression,signaling pathway intervention and programmed cell death.Besides,numerous new target drugs(microRNA inhibitors or agonists)have been proposed to exploit its value in skeletal physiology and pathology.In this review,we mainly discuss the role of microRNAs in the context of skeletal disease-associated osteoblast differentiation,the applications of microRNA polymorphisms as biomarkers for diagnostic and therapeutic targets,and the challenges to meet this goal.Our summary provides novel horizon for improving the therapeutic effect of microRNAs,which may be beneficial to the further clinical translation of microRNAs in the treatments of skeletal diseases.
