Osteoporosis is caused by an osteoclast activation mechanism.People suffering from osteoporosis are prone to bone defects.Increasing evidence indicates that scavenging reactive oxygen species(ROS)can inhibit receptor ...Osteoporosis is caused by an osteoclast activation mechanism.People suffering from osteoporosis are prone to bone defects.Increasing evidence indicates that scavenging reactive oxygen species(ROS)can inhibit receptor activator of nuclear factorκB ligand(RANKL)-induced osteoclastogenesis and suppress ovariectomy-induced osteoporosis.It is critical to develop biomaterials with antioxidant properties to modulate osteoclast activity for treating osteoporotic bone defects.Previous studies have shown that manganese(Mn)can improve bone regeneration,and Mn supplementation may treat osteoporosis.However,the effect of Mn on osteoclasts and the role of Mn in osteoporotic bone defects remain unclear.In present research,a model bioceramic,Mn-containedβ-tricalcium phosphate(Mn-TCP)was prepared by introducing Mn intoβ-TCP.The introduction of Mn intoβ-TCP significantly improved the scavenging of oxygen radicals and nitrogen radicals,demonstrating that Mn-TCP bioceramics might have antioxidant properties.The in vitro and in vivo findings revealed that Mn^(2+)ions released from Mn-TCP bioceramics could distinctly inhibit the formation and function of osteoclasts,promote the differentiation of osteoblasts,and accelerate bone regeneration under osteoporotic conditions in vivo.Mechanistically,Mn-TCP bioceramics inhibited osteoclastogenesis and promoted the regeneration of osteoporotic bone defects by scavenging ROS via Nrf2 activation.These results suggest that Mn-containing bioceramics with osteoconductivity,ROS scavenging and bone resorption inhibition abilities may be an ideal biomaterial for the treatment of osteoporotic bone defect.展开更多
Background The cannabinoid receptor-2 （CB2） is important for bone remodeling. In this study, we investigated the effects of CB2 selective antagonist （AM630） on receptor activator of nuclear factor kappa B （RANK）...Background The cannabinoid receptor-2 （CB2） is important for bone remodeling. In this study, we investigated the effects of CB2 selective antagonist （AM630） on receptor activator of nuclear factor kappa B （RANK） ligand （RANKL）induced osteoclast differentiation and the underlying signaling pathway using a monocyte-macrophage cell line-RAW264.7.Methods RAW264.7 was cultured with RANKL for 6 days and then treated with AM630 for 24 hours. Mature osteoclasts were measured by tartrate-resistant acid phosphatase （TRAP） staining using a commercial kit. Total ribonucleic acid （RNA）was isolated and real-time reverse transcriptase-polymerase chain reaction （RT-PCR） was done to examine the expression of RANK, cathepsin K （CPK） and nuclear factor kappa B （NF-κB）. The extracellular signal-regulated kinase （ERK）,phosphorylation of ERK （P-ERK） and NF-κB production were tested by Western blotting. The effect of AM630 on RAW264.7 viability was determined using the 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazoliumbromide （MTT） assay.Results AM630 did not affect the viability of RAW264.7. However, this CB2 selective antagonist markedly inhibited osteoclast formation and the inhibition rate was dose-dependent. The dose of 〉100 nmol/L could reduce TRAP positive cells to the levels that were significantly lower than the control. AM630 suppressed the expression of genes associated with osteoclast differentiation and activation, such as RANK and CPK. An analysis of a signaling pathway showed that AM630 inhibited the RANKL-induced activation of ERK, but not NF-κB.Conclusion AM630 could inhibit the osteoclastogenesis from RAW264.7 induced with RANKL.展开更多
Osteoporosis is a serious public bone metabolic disease. However, the mechanisms underlying bone loss combined with ageing, which is known as senile osteoporosis, remains unknown. Here we show the detailed phenotype o...Osteoporosis is a serious public bone metabolic disease. However, the mechanisms underlying bone loss combined with ageing, which is known as senile osteoporosis, remains unknown. Here we show the detailed phenotype of this disease caused by SIRT6 knock out （KO） in mice. To the best of our knowledge, this is the first study to reveal that SIRT6 is expressed in both bone marrow stroma cells and bone-related cells in both mouse and human models, which suggests that SIRT6 is an important regulator in bone metabolism. SIRT6-KO mice exhibit a significant decrease in body weight and remarkable dwarfism. The skeleton of the SIRT6-KO mouse is deficient in cartilage and mineralized bone tissue. Moreover, the osteocalcin concentration in blood is lower, which suggests that bone mass is markedly lost. Besides, the tartrate-resistant acid phosphatase 5b （TRAP5b） concentration is much higher, which suggests that bone resorption is overactive. Both trabecular and cortical bones exhibit severe osteopenia, and the bone mineral density is decreased. Moreover, double-labelling analysis shows that bone formation is much slower. To determine whether SIRT6 directly regulates bone metabolism, we cultured primary bone marrow stromal cells for osteogenesis and osteoclastogenesis separately to avoid indirect interference in vivo responses such as inflammation. Taken together, these results show that SIRT6 can directly regulate osteoblast proliferation and differentiation, resulting in attenuation in mineralization. Furthermore, SIRT6 can directly regulate osteoclast differentiation and results in a higher number of small osteoclasts, which may be related to overactive bone resorption.展开更多
全球范围内有数亿人口患有骨质疏松和类风湿性关节炎等与骨相关的疾病。对骨代谢发生分子机制的理解对于开发、研制治疗这些疾病的新药十分必要。遗传实验显示:核因子-κB受体性活化因子(receptor activator of NF-κB,RANK)、其配体RA...全球范围内有数亿人口患有骨质疏松和类风湿性关节炎等与骨相关的疾病。对骨代谢发生分子机制的理解对于开发、研制治疗这些疾病的新药十分必要。遗传实验显示:核因子-κB受体性活化因子(receptor activator of NF-κB,RANK)、其配体RANKL和诱饵受体OPG是破骨细胞发育和功能活化的关键调节物,这些研究结果是我们理解骨性疾病的一个重要转折点。RANKL-RANK信号传导可以激活破骨细胞发育所需的一系列下游信号途径。再者,在正常生理和疾病过程中,RANKL-RANK和其他配体-受体系统间的分子交叉串扰(cross-talk)精确调节着骨的动态平衡(homeostasis)。设计靶向针对破骨细胞中RANKL-RANK和他们的信号传导途径的药物可以成为革新许多治疗与骨丢失相关疾病(诸如关节炎、牙齿脱落、癌症转移或骨质疏松等)的新方法。展开更多
Bone remodeling is balanced by bone formation and bone resorption as well as by alterations in the quantities and functions of seed cells, leading to either the maintenance or deterioration of bone status. The existin...Bone remodeling is balanced by bone formation and bone resorption as well as by alterations in the quantities and functions of seed cells, leading to either the maintenance or deterioration of bone status. The existing evidence indicates that micro RNAs（mi RNAs）, known as a family of short non-coding RNAs, are the key post-transcriptional repressors of gene expression,and growing numbers of novel mi RNAs have been verified to play vital roles in the regulation of osteogenesis, osteoclastogenesis,and adipogenesis, revealing how they interact with signaling molecules to control these processes. This review summarizes the current knowledge of the roles of mi RNAs in regulating bone remodeling as well as novel applications for mi RNAs in biomaterials for therapeutic purposes.展开更多
Wnt通路在骨细胞的分化成熟、增殖更新和代谢中发挥重要作用。Wnt通路层级结构并不复杂,但参与通路活动的因子众多,包括数种低密度脂蛋白受体相关蛋白(low density lipoprotein receptor-related protein,LRP),19种的Wnt蛋白和10种卷曲...Wnt通路在骨细胞的分化成熟、增殖更新和代谢中发挥重要作用。Wnt通路层级结构并不复杂,但参与通路活动的因子众多,包括数种低密度脂蛋白受体相关蛋白(low density lipoprotein receptor-related protein,LRP),19种的Wnt蛋白和10种卷曲蛋白受体(frizzled receptor,FZD),还有多种非经典Wnt通路和抑制剂。Wnt蛋白家族结合细胞表面受体,启动经典Wnt通路或非经典Wnt通路下游信号发挥生理作用,不同蛋白对骨细胞分化方向和成骨活性或破骨活性的影响并不一致。文中主要对Wnt蛋白家族和Wnt通路对骨细胞分化、增殖和代谢活动的影响以及信号传导机制进行分析总结,概述Wnt蛋白家族对骨细胞活动和骨病的发生的影响及针对性药物的研究进展。展开更多
Bone tissue regeneration in critical-size defects is possible after implantation of a 3D scaffold and can be additionally enhanced once the scaffold is enriched with drugs or other factors supporting bone remodelling ...Bone tissue regeneration in critical-size defects is possible after implantation of a 3D scaffold and can be additionally enhanced once the scaffold is enriched with drugs or other factors supporting bone remodelling and healing.Sodium alendronate(Aln),a widely used anti-osteoporosis drug,exhibits strong inhibitory effect on bone resorption performed by osteoclasts.Thus,we propose a new approach for the treatment of bone defects in craniofacial region combining biocompatible titanium dioxide scaffolds and poly(L-lactide-co-glycolide)microparticles(MPs)loaded with Aln.The MPs were effectively attached to the surface of the scaffolds’pore walls by human recombinant collagen.Drug release from the scaffolds was characterized by initial burst(2466% of the drug released within first 24 h)followed by a sustained release phase(on average 5 mg of Aln released per day from Day 3 to Day 18).In vitro tests evidenced that Aln at concentrations of 5 and 2.5 mg/ml was not cytotoxic for MG-63 osteoblast-like cells(viability between 8166% and 9863% of control),but it prevented RANKL-induced formation of osteoclast-like cells from macrophages derived from peripheral blood mononuclear cells,as shown by reduced fusion capability and decreased tartrateresistant acid phosphatase 5b activity(5665% reduction in comparison to control after 8 days of culture).Results show that it is feasible to design the scaffolds providing required doses of Aln inhibiting osteoclastogenesis,reducing osteoclast activity,but not affecting osteoblast functions,which may be beneficial in the treatment of critical-size bone tissue defects.展开更多
Currently,implant-associated bacterial infections account for most hospital-acquired infections in patients suffering from bone fractures or defects.Poor osseointegration and aggravated osteolysis remain great challen...Currently,implant-associated bacterial infections account for most hospital-acquired infections in patients suffering from bone fractures or defects.Poor osseointegration and aggravated osteolysis remain great challenges for the success of implants in infectious scenarios.Consequently,developing an effective surface modification strategy for implants is urgently needed.Here,a novel nanoplatform(GO/Ga)consisting of graphene oxide(GO)and gallium nanoparticles(GaNPs)was reported,followed by investigations of its in vitro antibacterial activity and potential bacterium inactivation mechanisms,cytocompatibility and regulatory actions on osteoblastogenesis and osteoclastogenesis.In addition,the possible molecular mechanisms underlying the regulatory effects of GO/Ga nanocomposites on osteoblast differentiation and osteoclast formation were clarified.Moreover,an in vivo infectious microenvironment was established in a rat model of implant-related femoral osteomyelitis to determine the therapeutic efficacy and biosafety of GO/Ga nanocomposites.Our results indicate that GO/Ga nanocomposites with excellent antibacterial potency have evident osteogenic potential and inhibitory effects on osteoclast differentiation by modulating the BMP/Smad,MAPK and NF-κB signaling pathways.The in vivo experiments revealed that the administration of GO/Ga nanocomposites significantly inhibited bone infections,reduced osteolysis,promoted osseointegration located in implant-bone interfaces,and resulted in satisfactory biocompatibility.In summary,this synergistic therapeutic system could accelerate the bone healing process in implant-associated infections and can significantly guide the future surface modification of implants used in bacteria-infected environments.展开更多
Mechanical loading is required for bone homeostasis,but the underlying mechanism is still unclear.Our previous studies revealed that the mechanical protein polycystin-1(PC1,encoded by Pkd1)is critical for bone formati...Mechanical loading is required for bone homeostasis,but the underlying mechanism is still unclear.Our previous studies revealed that the mechanical protein polycystin-1(PC1,encoded by Pkd1)is critical for bone formation.However,the role of PC1 in bone resorption is unknown.Here,we found that PC1directly regulates osteoclastogenesis and bone resorption.The conditional deletion of Pkd1 in the osteoclast lineage resulted in a reduced number of osteoclasts,decreased bone resorption,and increased bone mass.A cohort study of 32,500 patients further revealed that autosomal dominant polycystic kidney disease,which is mainly caused by loss-of-function mutation of the PKD1 gene,is associated with a lower risk of hip fracture than those with other chronic kidney diseases.Moreover,mice with osteoclastspecific knockout of Pkd1 showed complete resistance to unloading-induced bone loss.A mechanistic study revealed that PC1 facilitated TAZ nuclear translocation via the C-terminal tail-TAZ complex and that conditional deletion of Taz in the osteoclast lineage resulted in reduced osteoclastogenesis and increased bone mass.Pharmacological regulation of the PC1-TAZ axis alleviated unloading-and estrogen deficiency-induced bone loss.Thus,the PC1-TAZ axis may be a potential therapeutic target for osteoclast-related osteoporosis.展开更多
Macrophages and osteoclasts are both derived from monocyte/macrophage lineage,which plays as the osteoclastic part of bone metabolism.Although they are regulated by bone implant surface nanoarchitecture and involved i...Macrophages and osteoclasts are both derived from monocyte/macrophage lineage,which plays as the osteoclastic part of bone metabolism.Although they are regulated by bone implant surface nanoarchitecture and involved in osseointegration,the beneath mechanism has not been simultaneously analyzed in a given surface model and their communication with osteoblasts is also blurring.Here,the effect of implant surface topography on monocyte/macrophage lineage osteoclastogenesis and the subsequent effect on osteogenesis are systematically investigated.The nanoporous surface is fabricated on titanium implant by etching and anodizing to get the nanotubes structure.The early bone formation around implant is significantly accelerated by the nanoporous surface in vivo.Meanwhile,the macrophage recruitment and osteoclast formation are increased and decreased respectively.Mechanistically,the integrin mediated FAK phosphorylation and its downstream MAPK pathway(p-p38)are significantly downregulated by the nanoporous surface,which account for the inhibition of osteoclastogenesis.In addition,the nanoporous surface can alleviate the inhibition of osteoclasts on osteogenesis by changing the secretion of clastokines,and accelerate bone regeneration by macrophage cytokine profiles.In conclusion,these data indicate that physical topography of implant surface is a critical factor modulating monocyte/macrophage lineage commitment,which provides theoretical guidance and mechanism basis for promoting osseointegration by coupling the osteogenesis and osteoclastogenesis.展开更多
基金the Key Program of National Natural Science Foundation of China(81930067)the Youth Program of National Natural Science Foundation of China(grant number 82002316)+1 种基金the Youth Cultivation Project of Army Medical University(2020XQN08)General Program of Natural Science Foundation of Chongqing(cstc2019jcyj-msxmX0176).
文摘Osteoporosis is caused by an osteoclast activation mechanism.People suffering from osteoporosis are prone to bone defects.Increasing evidence indicates that scavenging reactive oxygen species(ROS)can inhibit receptor activator of nuclear factorκB ligand(RANKL)-induced osteoclastogenesis and suppress ovariectomy-induced osteoporosis.It is critical to develop biomaterials with antioxidant properties to modulate osteoclast activity for treating osteoporotic bone defects.Previous studies have shown that manganese(Mn)can improve bone regeneration,and Mn supplementation may treat osteoporosis.However,the effect of Mn on osteoclasts and the role of Mn in osteoporotic bone defects remain unclear.In present research,a model bioceramic,Mn-containedβ-tricalcium phosphate(Mn-TCP)was prepared by introducing Mn intoβ-TCP.The introduction of Mn intoβ-TCP significantly improved the scavenging of oxygen radicals and nitrogen radicals,demonstrating that Mn-TCP bioceramics might have antioxidant properties.The in vitro and in vivo findings revealed that Mn^(2+)ions released from Mn-TCP bioceramics could distinctly inhibit the formation and function of osteoclasts,promote the differentiation of osteoblasts,and accelerate bone regeneration under osteoporotic conditions in vivo.Mechanistically,Mn-TCP bioceramics inhibited osteoclastogenesis and promoted the regeneration of osteoporotic bone defects by scavenging ROS via Nrf2 activation.These results suggest that Mn-containing bioceramics with osteoconductivity,ROS scavenging and bone resorption inhibition abilities may be an ideal biomaterial for the treatment of osteoporotic bone defect.
基金This work was supported by the grants from Jiangsu Province Key Medical Center （No. ZX200608）, the National Nature Science Foundation of China （No. 30672140, No. 81071451）, the Colleges and Universities Natural Science Foundation in Jiangsu Province （No. 10KJB320019）, the Key Project Surpported by the Medical Science and Technology Department Foundation, Jiangsu Province, Department of Health （No. H201012） and the Social Development Projects in Suzhou （No. SS08020）.
文摘Background The cannabinoid receptor-2 （CB2） is important for bone remodeling. In this study, we investigated the effects of CB2 selective antagonist （AM630） on receptor activator of nuclear factor kappa B （RANK） ligand （RANKL）induced osteoclast differentiation and the underlying signaling pathway using a monocyte-macrophage cell line-RAW264.7.Methods RAW264.7 was cultured with RANKL for 6 days and then treated with AM630 for 24 hours. Mature osteoclasts were measured by tartrate-resistant acid phosphatase （TRAP） staining using a commercial kit. Total ribonucleic acid （RNA）was isolated and real-time reverse transcriptase-polymerase chain reaction （RT-PCR） was done to examine the expression of RANK, cathepsin K （CPK） and nuclear factor kappa B （NF-κB）. The extracellular signal-regulated kinase （ERK）,phosphorylation of ERK （P-ERK） and NF-κB production were tested by Western blotting. The effect of AM630 on RAW264.7 viability was determined using the 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazoliumbromide （MTT） assay.Results AM630 did not affect the viability of RAW264.7. However, this CB2 selective antagonist markedly inhibited osteoclast formation and the inhibition rate was dose-dependent. The dose of 〉100 nmol/L could reduce TRAP positive cells to the levels that were significantly lower than the control. AM630 suppressed the expression of genes associated with osteoclast differentiation and activation, such as RANK and CPK. An analysis of a signaling pathway showed that AM630 inhibited the RANKL-induced activation of ERK, but not NF-κB.Conclusion AM630 could inhibit the osteoclastogenesis from RAW264.7 induced with RANKL.
基金supported by NSFC grants 81371136 and JCPT2011-9 (Xue-Dong Zhou),NSFC grants 81470711 and 81200760 (Li-Wei Zheng)Ling Ye (Professor, Sate Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University) for financial aid
文摘Osteoporosis is a serious public bone metabolic disease. However, the mechanisms underlying bone loss combined with ageing, which is known as senile osteoporosis, remains unknown. Here we show the detailed phenotype of this disease caused by SIRT6 knock out （KO） in mice. To the best of our knowledge, this is the first study to reveal that SIRT6 is expressed in both bone marrow stroma cells and bone-related cells in both mouse and human models, which suggests that SIRT6 is an important regulator in bone metabolism. SIRT6-KO mice exhibit a significant decrease in body weight and remarkable dwarfism. The skeleton of the SIRT6-KO mouse is deficient in cartilage and mineralized bone tissue. Moreover, the osteocalcin concentration in blood is lower, which suggests that bone mass is markedly lost. Besides, the tartrate-resistant acid phosphatase 5b （TRAP5b） concentration is much higher, which suggests that bone resorption is overactive. Both trabecular and cortical bones exhibit severe osteopenia, and the bone mineral density is decreased. Moreover, double-labelling analysis shows that bone formation is much slower. To determine whether SIRT6 directly regulates bone metabolism, we cultured primary bone marrow stromal cells for osteogenesis and osteoclastogenesis separately to avoid indirect interference in vivo responses such as inflammation. Taken together, these results show that SIRT6 can directly regulate osteoblast proliferation and differentiation, resulting in attenuation in mineralization. Furthermore, SIRT6 can directly regulate osteoclast differentiation and results in a higher number of small osteoclasts, which may be related to overactive bone resorption.
文摘全球范围内有数亿人口患有骨质疏松和类风湿性关节炎等与骨相关的疾病。对骨代谢发生分子机制的理解对于开发、研制治疗这些疾病的新药十分必要。遗传实验显示:核因子-κB受体性活化因子(receptor activator of NF-κB,RANK)、其配体RANKL和诱饵受体OPG是破骨细胞发育和功能活化的关键调节物,这些研究结果是我们理解骨性疾病的一个重要转折点。RANKL-RANK信号传导可以激活破骨细胞发育所需的一系列下游信号途径。再者,在正常生理和疾病过程中,RANKL-RANK和其他配体-受体系统间的分子交叉串扰(cross-talk)精确调节着骨的动态平衡(homeostasis)。设计靶向针对破骨细胞中RANKL-RANK和他们的信号传导途径的药物可以成为革新许多治疗与骨丢失相关疾病(诸如关节炎、牙齿脱落、癌症转移或骨质疏松等)的新方法。
基金supported by grants from the Science and Technology Fund of Sichuan Province (Grant No. 2011SZ0096)the National Natural Science Foundation of China (Grant No. 31470904)
文摘Bone remodeling is balanced by bone formation and bone resorption as well as by alterations in the quantities and functions of seed cells, leading to either the maintenance or deterioration of bone status. The existing evidence indicates that micro RNAs（mi RNAs）, known as a family of short non-coding RNAs, are the key post-transcriptional repressors of gene expression,and growing numbers of novel mi RNAs have been verified to play vital roles in the regulation of osteogenesis, osteoclastogenesis,and adipogenesis, revealing how they interact with signaling molecules to control these processes. This review summarizes the current knowledge of the roles of mi RNAs in regulating bone remodeling as well as novel applications for mi RNAs in biomaterials for therapeutic purposes.
基金supported by National Science Centre,Poland(2013/09/N/ST8/00309)Norwegian Research Council(228415)BMBF,Germany(GoBone German-Polish bilateral project 01DS16010A).
文摘Bone tissue regeneration in critical-size defects is possible after implantation of a 3D scaffold and can be additionally enhanced once the scaffold is enriched with drugs or other factors supporting bone remodelling and healing.Sodium alendronate(Aln),a widely used anti-osteoporosis drug,exhibits strong inhibitory effect on bone resorption performed by osteoclasts.Thus,we propose a new approach for the treatment of bone defects in craniofacial region combining biocompatible titanium dioxide scaffolds and poly(L-lactide-co-glycolide)microparticles(MPs)loaded with Aln.The MPs were effectively attached to the surface of the scaffolds’pore walls by human recombinant collagen.Drug release from the scaffolds was characterized by initial burst(2466% of the drug released within first 24 h)followed by a sustained release phase(on average 5 mg of Aln released per day from Day 3 to Day 18).In vitro tests evidenced that Aln at concentrations of 5 and 2.5 mg/ml was not cytotoxic for MG-63 osteoblast-like cells(viability between 8166% and 9863% of control),but it prevented RANKL-induced formation of osteoclast-like cells from macrophages derived from peripheral blood mononuclear cells,as shown by reduced fusion capability and decreased tartrateresistant acid phosphatase 5b activity(5665% reduction in comparison to control after 8 days of culture).Results show that it is feasible to design the scaffolds providing required doses of Aln inhibiting osteoclastogenesis,reducing osteoclast activity,but not affecting osteoblast functions,which may be beneficial in the treatment of critical-size bone tissue defects.
基金Our study was financially supported by the National Natural Science Fundation for Youth of China(Nos.81802136)the Natural Science Fundation for Youth of Hunan Province(Nos.2020JJ5939)+2 种基金the Postdoctoral Science Fundation of China(Nos.2018M643005)the National Natural Science Fundation of China(Nos.52172265)the Science Fundation for Youth of Xiangya Hospital,Central South University(Nos.2017Q18).
文摘Currently,implant-associated bacterial infections account for most hospital-acquired infections in patients suffering from bone fractures or defects.Poor osseointegration and aggravated osteolysis remain great challenges for the success of implants in infectious scenarios.Consequently,developing an effective surface modification strategy for implants is urgently needed.Here,a novel nanoplatform(GO/Ga)consisting of graphene oxide(GO)and gallium nanoparticles(GaNPs)was reported,followed by investigations of its in vitro antibacterial activity and potential bacterium inactivation mechanisms,cytocompatibility and regulatory actions on osteoblastogenesis and osteoclastogenesis.In addition,the possible molecular mechanisms underlying the regulatory effects of GO/Ga nanocomposites on osteoblast differentiation and osteoclast formation were clarified.Moreover,an in vivo infectious microenvironment was established in a rat model of implant-related femoral osteomyelitis to determine the therapeutic efficacy and biosafety of GO/Ga nanocomposites.Our results indicate that GO/Ga nanocomposites with excellent antibacterial potency have evident osteogenic potential and inhibitory effects on osteoclast differentiation by modulating the BMP/Smad,MAPK and NF-κB signaling pathways.The in vivo experiments revealed that the administration of GO/Ga nanocomposites significantly inhibited bone infections,reduced osteolysis,promoted osseointegration located in implant-bone interfaces,and resulted in satisfactory biocompatibility.In summary,this synergistic therapeutic system could accelerate the bone healing process in implant-associated infections and can significantly guide the future surface modification of implants used in bacteria-infected environments.
基金supported by the National Key Research and Development Program of China(2019YFA0111900,2022YFC3601900 and 2022YFC2505500)the National Natural Science Foundation of China(82261160397,82272560,81922017,92149306 and 82120108009)+5 种基金the NSFC/RGC Joint Research Schemethe Research Grants Council(UGC)of the Hong Kong Special Administrative Region and the National Natural Science Foundation of China(N_CUHK483/22)the Center for Neuromusculoskeletal Restorative Medicine by Innovation and Technology Commission(ITC)of Hong Kong SAR,China(CNRM at Inno HK),the National Institutes of Health(R61-AR073518 and R01-AR071930)the Key Research and Development Program of Hunan Province(2022SK2023)the Science and Technology Innovation Program of Hunan Province(2023RC1027,2022RC1009 and 2022RC3075)the Hunan Provincial Science and Technology Department(2023JJ30896)。
文摘Mechanical loading is required for bone homeostasis,but the underlying mechanism is still unclear.Our previous studies revealed that the mechanical protein polycystin-1(PC1,encoded by Pkd1)is critical for bone formation.However,the role of PC1 in bone resorption is unknown.Here,we found that PC1directly regulates osteoclastogenesis and bone resorption.The conditional deletion of Pkd1 in the osteoclast lineage resulted in a reduced number of osteoclasts,decreased bone resorption,and increased bone mass.A cohort study of 32,500 patients further revealed that autosomal dominant polycystic kidney disease,which is mainly caused by loss-of-function mutation of the PKD1 gene,is associated with a lower risk of hip fracture than those with other chronic kidney diseases.Moreover,mice with osteoclastspecific knockout of Pkd1 showed complete resistance to unloading-induced bone loss.A mechanistic study revealed that PC1 facilitated TAZ nuclear translocation via the C-terminal tail-TAZ complex and that conditional deletion of Taz in the osteoclast lineage resulted in reduced osteoclastogenesis and increased bone mass.Pharmacological regulation of the PC1-TAZ axis alleviated unloading-and estrogen deficiency-induced bone loss.Thus,the PC1-TAZ axis may be a potential therapeutic target for osteoclast-related osteoporosis.
基金supported by National Natural Science Foundation of China(81530051,31800790 and 32071324)Young Talent Fund of University Association for Science and Technology in Shaanxi,China(20190304).
文摘Macrophages and osteoclasts are both derived from monocyte/macrophage lineage,which plays as the osteoclastic part of bone metabolism.Although they are regulated by bone implant surface nanoarchitecture and involved in osseointegration,the beneath mechanism has not been simultaneously analyzed in a given surface model and their communication with osteoblasts is also blurring.Here,the effect of implant surface topography on monocyte/macrophage lineage osteoclastogenesis and the subsequent effect on osteogenesis are systematically investigated.The nanoporous surface is fabricated on titanium implant by etching and anodizing to get the nanotubes structure.The early bone formation around implant is significantly accelerated by the nanoporous surface in vivo.Meanwhile,the macrophage recruitment and osteoclast formation are increased and decreased respectively.Mechanistically,the integrin mediated FAK phosphorylation and its downstream MAPK pathway(p-p38)are significantly downregulated by the nanoporous surface,which account for the inhibition of osteoclastogenesis.In addition,the nanoporous surface can alleviate the inhibition of osteoclasts on osteogenesis by changing the secretion of clastokines,and accelerate bone regeneration by macrophage cytokine profiles.In conclusion,these data indicate that physical topography of implant surface is a critical factor modulating monocyte/macrophage lineage commitment,which provides theoretical guidance and mechanism basis for promoting osseointegration by coupling the osteogenesis and osteoclastogenesis.
