Complement C3 plays a critical role in periodontitis.However,its source,role and underlying mechanisms remain unclear.In our study,by analyzing single-cell sequencing data from mouse model of periodontitis,we identifi...Complement C3 plays a critical role in periodontitis.However,its source,role and underlying mechanisms remain unclear.In our study,by analyzing single-cell sequencing data from mouse model of periodontitis,we identified that C3 is primarily derived from periodontal fibroblasts.Subsequently,we demonstrated that C3a has a detrimental effect in ligature-induced periodontitis.C3ar−/−mice exhibited significantly less destruction of periodontal support tissues compared to wild-type mice,characterized by mild gingival tissue damage and reduced alveolar bone loss.This reduction was associated with decreased production of proinflammatory mediators and reduced osteoclast infiltration in the periodontal tissues.Mechanistic studies suggested that C3a could promote macrophage polarization and osteoclast differentiation.Finally,by analyzing single-cell sequencing data from the periodontal tissues of patients with periodontitis,we found that the results observed in mice were consistent with human data.Therefore,our findings clearly demonstrate the destructive role of fibroblast-derived C3 in ligature-induced periodontitis,driven by macrophage M1 polarization and osteoclast differentiation.These data strongly support the feasibility of C3a-targeted interventions for the treatment of human periodontitis.展开更多
BACKGROUND This study analyzed the dental follicle and alveolar bone of two patients with tooth eruption disorders,aiming to provide some reference for exploring the etiology and selecting treatment plans of this dise...BACKGROUND This study analyzed the dental follicle and alveolar bone of two patients with tooth eruption disorders,aiming to provide some reference for exploring the etiology and selecting treatment plans of this disease from the perspective of the influence of extracellular matrix on osteoclasts differentiation in dental follicle.CASE SUMMARY Collect dental follicle and alveolar bone tissue from one patient with single tooth eruption disorder and one patient with full permanent tooth eruption disorder,respectively.Simultaneously collect the dental follicle and alveolar bone tissue of obstructed teeth that need to be extracted due to orthodontic treatment as the control group.Hematoxylin and eosin(HE)staining was used to observe the morphology of dental follicle cells.Immunohistochemical staining was used to observe the expression of periostin,receptor activator of nuclear factor kappa B ligand(RANKL),and osteoprotegerin(OPG)protein in dental follicle and alveolar bone tissue.And observe the eruption of teeth after removing resistance from the crown of the permanent tooth germ.CONCLUSION HE staining of two cases of dental follicle tissues showed that the volume of dental follicle cells decreased,the nuclei were condensed,and there seemed to be cellular fibrosis.The immunohistochemical staining showed that both the dental follicle and alveolar bone tissue exhibited increased expression of periostin,decreased expression of RANKL and OPG proteins,and decreased RANKL/OPG ratio.After removing resistance,the permanent tooth germ often appears to have normal eruption.Tooth eruption disorders may be accompanied by abnormal remodeling of periostin,which affects the differentiation function of osteoclasts in the dental follicle and leads to metabolic imbalance of alveolar bone,resulting in tooth eruption disorders.Whether it is a single or full permanent tooth eruption disorder,once the coronal resistance is removed,the teeth can often erupt normally.展开更多
We demonstrate a simple,effective and feasible method to address the shrinkage of Poly(lactic-co-glycolic acid)(PLGA)through a core-shell structure fiber strategy.The results revealed that introducing size-stable poly...We demonstrate a simple,effective and feasible method to address the shrinkage of Poly(lactic-co-glycolic acid)(PLGA)through a core-shell structure fiber strategy.The results revealed that introducing size-stable poly-caprolactone(PCL)as the core fiber significantly improved the PLGA-based fibrous scaffold’s dimensional maintenance.We further utilized fish collagen to modify the PLGA shell layer(PFC)of coaxial fibers and loaded baicalin(BA)into the PCL core layer(PCL-BA)to endow fibrous scaffold with more functional biological cues.The PFC/PCL-BA fibrous scaffold promoted the osteogenic differentiation of bone mesenchymal stem cells and stimulated the RAW264.7 cells to polarize into a pro-reparative phenotype.Importantly,the in vivo study demonstrated that the PFC/PCL-BA scaffold could regulate inflammation and osteoclast differentiation,favor neovascularization and bone formation.This work tactfully combined PLGA and PCL to establish a drug release platform based on the core-shell fibrous scaffold for vascularized bone regeneration.展开更多
Objective： To study the mechanism underlying the inhibitory effect of Qingluo Tongbi Granule （清络通痹颗粒, QTG） on osteoclast differentiation in rheumatoid arthritis in rats. Methods： Fibroblast and monocyte co-c...Objective： To study the mechanism underlying the inhibitory effect of Qingluo Tongbi Granule （清络通痹颗粒, QTG） on osteoclast differentiation in rheumatoid arthritis in rats. Methods： Fibroblast and monocyte co-culture were used to induce osteoclast differentiation in adjuvant-induced arthritic （AIA） rats. Serum containing QTG was prepared and added to the osteoclasts, and activation of the tumor necrosis factor receptorassociated factor 6/mitogen-activated protein kinase/nuclear factor of activated T cells, cytoplasmic1 （TRAF6/ MAPK/NFATcl） pathways was examined. Results： The induced osteoclasts were multinucleated and stained positive for tartrate-resistant acid phosphatase （TRAP） staining. Serum containing QTG at 14.4, 7.2 or 3.6 g/kg inhibited the activation of TRAF6, extracellular regulated protein kinase （ERK）1/2, c-Jun N-terminal kinase （JNK） and p38 and decreased the percentage of cells with nuclear NFATcl in a dose-dependent manner, the high and middle doses exhibited clear inhibitory activity （P〈0.01 and P〈0.05, respectively）. After the addition of MAPK inhibitors, the NFATcl expression showed no significant difference compared with the control group （P〉0.05）. Conclusions： Serum containing QTG could generally inhibit the TRAF6/MAPK pathways and possibly inhibit the NFATcl pathway. In addition, QTG may regulate other signaling pathways that are related to osteoclast differentiation and maturation.展开更多
Osteoclasts,which are derived from monocyte-macrophage precursors,are exclusive bone resorption cells.Limited evidence indicates that a class of small non-coding single-stranded RNAs known as“microRNAs”(miRNAs)is al...Osteoclasts,which are derived from monocyte-macrophage precursors,are exclusive bone resorption cells.Limited evidence indicates that a class of small non-coding single-stranded RNAs known as“microRNAs”(miRNAs)is also involved in bone resorption.Although various miRNAs regulate cell proliferation and differentiation,few miRNAs have been reported to play a key role in the regulation of osteoclast differentiation.In this short review,the biology and functional mechanisms of miRNAs in osteoclastogenesis are summarized.The profiling,function,and target prediction of miRNAs are discussed as well.展开更多
The pathogenic effects of type 2 diabetes on bone tissue are gaining attention,but the cellular and molecular mechanisms underlying osteoimmunology are still unclear in diabetes-related bone diseases.We delineated the...The pathogenic effects of type 2 diabetes on bone tissue are gaining attention,but the cellular and molecular mechanisms underlying osteoimmunology are still unclear in diabetes-related bone diseases.We delineated the single-cell transcriptome of bone marrow cells from both wide type and type 2 diabetes mice,which provided the first detailed global profile of bone marrow cells and revealed a distinct bone immune microenvironment at the genetic level under type 2 diabetic condition.It was observed that osteoclast activity was inhibited due to a dysre-gulated cytokine network,which ultimately led to decreased osteoclast formation and differen-tiation.In type 2 diabetes mice,a specific Cd36+cluster(cluster 18,monocytes/macrophages 2)was identified as the precursor of osteoclasts with diminished differentiation potential.AP-1 was demonstrated to be the key transcription factor in the underlying mechanism.展开更多
To dissect which subset of bone marrow monocyte is the major precursor of osteoclast,3-month-old rat bone marrow was obtained for single-cell RNA sequencing.A total of 6091 cells were acquired for detailed analysis,wi...To dissect which subset of bone marrow monocyte is the major precursor of osteoclast,3-month-old rat bone marrow was obtained for single-cell RNA sequencing.A total of 6091 cells were acquired for detailed analysis,with a median number of 1206 genes detected per cell and 17,959 genes detected in total.A total of 19 cell clusters were recognized,with the main lineages identified as B cells,Granulocytes,Monocytes,T cells,Erythrocytes and Macrophages.Monocytes were further divided into classical monocytes and non-classical monocytes.Compared with non-classical monocytes,classical monocytes highly expressed osteoclast differentiation related genes Mitf,Spi1,Fos and Csf1r.Additionally,biological processes of classical monocytes were related to osteoclast differentiation.qPCR revealed differentially expressed genes of classical monocytes played a role in osteoclast differentiation.In conclusion,classical monocytes were identified as the main precursors of osteoclasts in rats,and may contribute to osteoclast differentiation by regulating S100a4,S100a6,S100a10,Fn1,Vcan and Bcl2a1.The results of this study contribute to the understanding of the origin of osteoclasts and may provide potential biomarkers for early diagnosis of bone metabolic diseases,as well as molecular and cellular targets for clinical intervention in bone metabolic diseases.展开更多
Osteoclasts(OCs)are responsible for bone resorption in inflammatory joint diseases.Monocyte chemotactic protein-1(MCP-1)has been shown to induce differentiation of monocytes to OC precursors,but nothing is known about...Osteoclasts(OCs)are responsible for bone resorption in inflammatory joint diseases.Monocyte chemotactic protein-1(MCP-1)has been shown to induce differentiation of monocytes to OC precursors,but nothing is known about the underlying mechanisms.Here,we elucidate how MCPIP,induced by MCP-1,mediates this differentiation.Knockdown of MCPIP abolished MCP-1-mediated expression of OC markers,tartrate-resistant acid phosphatase,and serine protease cathepsin K.Expression of MCPIP induced p47PHOX and its membrane translocation,reactive oxygen species formation,and induction of endoplasmic reticulum(ER)stress chaperones,up-regulation of autophagy marker,Beclin-1,and lipidation of LC3,and induction of OC markers.Inhibition of oxidative stress attenuated ER stress and autophagy,and suppressed expression of OC markers.Inhibition of ER stress by a specific inhibitor or by knockdown of IRE1 blocked autophagy and induction of OC markers.ER stress inducers,tunicamycin and thapsigargin,induced expression of OC markers.Autophagy inhibition by 3′-methyladenine,LY294002,wortmannin or by knockdown of Beclin-1 or Atg 7 inhibited MCPIP-induced expression of OC markers.These results strongly suggest that MCP-1-induced differentiation of OC precursor cells is mediated via MCPIP-induced oxidative stress that causes ER stress leading to autophagy,revealing a novel mechanistic insight into the role of MCP-1 in OCs differentiation.展开更多
PIP5k1βis crucial to the generation of phosphotidylinosotol(4,5)P2.PIP5k1βparticipates in numerous cellular activities,such as B cell and platelet activation,cell phagocytosis and endocytosis,cell apoptosis,and cyto...PIP5k1βis crucial to the generation of phosphotidylinosotol(4,5)P2.PIP5k1βparticipates in numerous cellular activities,such as B cell and platelet activation,cell phagocytosis and endocytosis,cell apoptosis,and cytoskeletal organization.In the present work,we aimed to examine the function of PIP5k1βin osteoclastogenesis and osteogenesis to provide promising strategies for osteoporosis prevention and treatment.We discovered that PIP5k1β deletion in mice resulted in obvious bone loss and that PIP5k1β was highly expressed during both osteoclast and osteoblast differentiation.Deletion of the gene was found to enhance the proliferation and migration of bone marrow-derived macrophage-like cells to promote osteoclast differentiation.PIP5k1β-/-osteoclasts exhibited normal cytoskeleton architecture but stronger resorption activity.PIP5kip deficiency also promoted activation of mitogen-activated kinase and Akt signaling,enhanced TRAF6 and c-Fos expression,facilitated the expression and nuclear translocation of NFATC1,and upregulated Grb2 expression,thereby accelerating osteoclast differentiation and function.Finally,PIP5k1β enhanced osteoblast differentiation by upregulating master gene expression through triggering smad1/5/8 signaling.Therefore,PIP5k1βmodulates bone homeostasis and remodeling.展开更多
Objective：To investigate the gene expression of osteoprotegerin（OPG） and osteoclast differentiation factor（ODF） in the bone tissue of patients with hip fracture due to osteoporosis. Methods：OPGmRNA and ODFmRNA i...Objective：To investigate the gene expression of osteoprotegerin（OPG） and osteoclast differentiation factor（ODF） in the bone tissue of patients with hip fracture due to osteoporosis. Methods：OPGmRNA and ODFmRNA in the bone tissue in 50 cases of osteoporosis sufferers（over 50 years old） with hip fracture（Observer Group） and 30 cases of hip facture sufferers with no osteoporosis（Control group） were analyzed with the Semi-Quantitative RT-PCR method. Results：The mRNA expressed of ODF, OPG were both high in the patients with hip fracture. In the control group, the expression of OPG mRNA was observed, while the expression of ODF mRNA was very slight. Conclusion：Aged patients contained all signals including OPG, ODF that are essential for inducing osteoclastogenesis and promoting bone resorption.展开更多
Osteoclast-like cells are known to inhibit arterial calcification. Receptor activator of NF-κB ligand（RANKL） is likely to act as an inducer of osteoclast-like cell differentiation. However,several studies have show...Osteoclast-like cells are known to inhibit arterial calcification. Receptor activator of NF-κB ligand（RANKL） is likely to act as an inducer of osteoclast-like cell differentiation. However,several studies have shown that RANKL promotes arterial calcification rather than inhibiting arterial calcification. The present study was conducted in order to investigate and elucidate this paradox. Firstly,RANKL was added into the media,and the monocyte precursor cells were cultured. Morphological observation and Tartrate resistant acid phosphatase（TRAP） staining were used to assess whether RANKL could induce the monocyte precursor cells to differentiate into osteoclast-like cells. During arterial calcification,in vivo and in vitro expression of RANKL and its inhibitor,osteoprotegerin（OPG）,was detected by real-time PCR. The extent of osteoclast-like cell differentiation was also assessed. It was found RANKL could induce osteoclast-like cell differentiation. There was no in vivo or in vitro expression of osteoclast-like cells in the early stage of calcification. At that time,the ratio of RANKL to OPG was very low. In the late stage of calcification,a small amount of osteoclast-like cell expression coincided with a relatively high ratio of RANKL to OPG. According to the results,the ratio of RANKL to OPG was very low during most of the arterial calcification period. This made it possible for OPG to completely inhibit RANKL-induced osteoclast-like cell differentiation. This likely explains why RANKL had the ability to induce osteoclast-like cell differentiation but acted as a promoter of calcification instead.展开更多
Background:Multiple myeloma(MM)is the second most common hematological malignancy.An overwhelming majority of patients with MM progress to serious osteolytic bone disease.Aminoacyl-tRNA synthetase-interacting multifun...Background:Multiple myeloma(MM)is the second most common hematological malignancy.An overwhelming majority of patients with MM progress to serious osteolytic bone disease.Aminoacyl-tRNA synthetase-interacting multifunctional protein 1(AIMP1)participates in several steps during cancer development and osteoclast differentiation.This study aimed to explore its role in MM.Methods:The gene expression profiling cohorts of MM were applied to determine the expression of AIMP1 and its association with MM patient prognosis.Enzyme-linked immunosorbent assay,immunohistochemistry,and Western blotting were used to detect AIMP1 expression.Protein chip analysis,RNA-sequencing,and chromatin immunoprecipitation and next-generation sequencing were employed to screen the interacting proteins and key downstream targets of AIMP1.The impact of AIMP1 on cellular proliferation was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay in vitro and a xenograft model in vivo.Bone lesions were evaluated using tartrate-resistant acid phosphatase staining in vitro.A NOD/SCID-TIBIA mouse model was used to evaluate the effect of siAIMP1-loaded exosomes on bone lesion formation in vivo.Results:AIMP1 expression was increased in MM patients and strongly associated with unfavorable outcomes.Increased AIMP1 expression promoted MM cell proliferation in vitro and in vivo via activation of the mitogen-activated protein kinase(MAPK)signaling pathway.Protein chip assays and subsequent experiments revealed that AIMP1 interacted with acidic leucine-rich nuclear phosphoprotein 32 family member A(ANP32A)to regulate histone H3 acetylation.In addition,AIMP1 increased histone H3 acetylation enrichment function of GRB2-associated and regulator of MAPK protein 2(GAREM2)to increase the phosphorylation of extracellular-regulated kinase 1/2(p-ERK1/2).Furthermore,AIMP1 promoted osteoclast differentiation by activating nuclear factor of activated T cells c1(NFATc1)in vitro.In contrast,exosome-coated small interfering RNA of AIMP1 effectively suppressed MM progression and osteoclast differentiation in vitro and in vivo.Conclusions:Our data demonstrate that AIMP1 is a novel regulator of histone H3 acetylation interacting with ANP32A in MM,which accelerates MM malignancy via activation of the MAPK signaling pathway.展开更多
Black phosphorus(BP)is a newly discovered two-dimensional material that has promising applications from bioelectronics to biomedicine.However,facile oxidation of BP leads to changes in surface chemical composition and...Black phosphorus(BP)is a newly discovered two-dimensional material that has promising applications from bioelectronics to biomedicine.However,facile oxidation of BP leads to changes in surface chemical composition and physical properties,often being referred to as the degradation process of BP.Degradation products of BP nanosheets,namely,oxidized BP nanosheets(oBPNSs),are routinely considered as by-products without many uses.Herein,we found that oBPNSs displayed excellent osteoclastogenesis inhibition effects without impairing cell viability.In contrast to the classic antiresorptive bisphosphonate drugs,oBPNSs showed a different mode of action by suppressing the maturation of osteoclasts.Bone resorption assays,osteoclast actin ring analysis,and tartrate-resistant acid phosphate activity assay results indicated that oBPNSs suppressed receptor activator of nuclear factor-κB(NF-κB)ligand(RANKL)-induced osteoclastogenesis in a dose-and oxidation-dependent manner.Transcriptomic and proteomic analyses indicated that oBPNSs inhibited the activation of the NF-κB signaling pathway and phosphorylation of mitogen-activated protein kinase(MAPK)in differentiated osteoclasts,as confirmed by Western blot analysis.Our results suggest that oBPNSs might be potential antiresorptive nanomaterials to treat osteoporosis.展开更多
基金supported by the National Key R&D Program of China(No.2022YFC2504200)the National Natural Science Foundation of China(Nos.82370936,81920108012,82471032).
文摘Complement C3 plays a critical role in periodontitis.However,its source,role and underlying mechanisms remain unclear.In our study,by analyzing single-cell sequencing data from mouse model of periodontitis,we identified that C3 is primarily derived from periodontal fibroblasts.Subsequently,we demonstrated that C3a has a detrimental effect in ligature-induced periodontitis.C3ar−/−mice exhibited significantly less destruction of periodontal support tissues compared to wild-type mice,characterized by mild gingival tissue damage and reduced alveolar bone loss.This reduction was associated with decreased production of proinflammatory mediators and reduced osteoclast infiltration in the periodontal tissues.Mechanistic studies suggested that C3a could promote macrophage polarization and osteoclast differentiation.Finally,by analyzing single-cell sequencing data from the periodontal tissues of patients with periodontitis,we found that the results observed in mice were consistent with human data.Therefore,our findings clearly demonstrate the destructive role of fibroblast-derived C3 in ligature-induced periodontitis,driven by macrophage M1 polarization and osteoclast differentiation.These data strongly support the feasibility of C3a-targeted interventions for the treatment of human periodontitis.
基金Supported by The Xuzhou Medical University Affiliated Hospital Development Fund Support Project,No.XYFM202457the 521 Scientific Research Project of Lianyungang City,No.LYG 06521202362.
文摘BACKGROUND This study analyzed the dental follicle and alveolar bone of two patients with tooth eruption disorders,aiming to provide some reference for exploring the etiology and selecting treatment plans of this disease from the perspective of the influence of extracellular matrix on osteoclasts differentiation in dental follicle.CASE SUMMARY Collect dental follicle and alveolar bone tissue from one patient with single tooth eruption disorder and one patient with full permanent tooth eruption disorder,respectively.Simultaneously collect the dental follicle and alveolar bone tissue of obstructed teeth that need to be extracted due to orthodontic treatment as the control group.Hematoxylin and eosin(HE)staining was used to observe the morphology of dental follicle cells.Immunohistochemical staining was used to observe the expression of periostin,receptor activator of nuclear factor kappa B ligand(RANKL),and osteoprotegerin(OPG)protein in dental follicle and alveolar bone tissue.And observe the eruption of teeth after removing resistance from the crown of the permanent tooth germ.CONCLUSION HE staining of two cases of dental follicle tissues showed that the volume of dental follicle cells decreased,the nuclei were condensed,and there seemed to be cellular fibrosis.The immunohistochemical staining showed that both the dental follicle and alveolar bone tissue exhibited increased expression of periostin,decreased expression of RANKL and OPG proteins,and decreased RANKL/OPG ratio.After removing resistance,the permanent tooth germ often appears to have normal eruption.Tooth eruption disorders may be accompanied by abnormal remodeling of periostin,which affects the differentiation function of osteoclasts in the dental follicle and leads to metabolic imbalance of alveolar bone,resulting in tooth eruption disorders.Whether it is a single or full permanent tooth eruption disorder,once the coronal resistance is removed,the teeth can often erupt normally.
基金supported by the National Key Research and Development Program of China(No.2016YFA0201703/2016YFA0201700)the Key R&D Project of Sichuan Science and Technology Plan(2021YFS0030).
文摘We demonstrate a simple,effective and feasible method to address the shrinkage of Poly(lactic-co-glycolic acid)(PLGA)through a core-shell structure fiber strategy.The results revealed that introducing size-stable poly-caprolactone(PCL)as the core fiber significantly improved the PLGA-based fibrous scaffold’s dimensional maintenance.We further utilized fish collagen to modify the PLGA shell layer(PFC)of coaxial fibers and loaded baicalin(BA)into the PCL core layer(PCL-BA)to endow fibrous scaffold with more functional biological cues.The PFC/PCL-BA fibrous scaffold promoted the osteogenic differentiation of bone mesenchymal stem cells and stimulated the RAW264.7 cells to polarize into a pro-reparative phenotype.Importantly,the in vivo study demonstrated that the PFC/PCL-BA scaffold could regulate inflammation and osteoclast differentiation,favor neovascularization and bone formation.This work tactfully combined PLGA and PCL to establish a drug release platform based on the core-shell fibrous scaffold for vascularized bone regeneration.
基金Supported by the National Natural Science Foundation of China(No.81072749)the Ministry of Education of Overseas Returnees Research Fund(No.2006331)+3 种基金Six Talent Peaks Subject of Jiangsu Province(No.2007)a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(No.20116)Jiangsu Province Ordinary University Innovative Research ProjectOrdinary University Innovative Research Project of Jiangsu Province(No.2011)
文摘Objective： To study the mechanism underlying the inhibitory effect of Qingluo Tongbi Granule （清络通痹颗粒, QTG） on osteoclast differentiation in rheumatoid arthritis in rats. Methods： Fibroblast and monocyte co-culture were used to induce osteoclast differentiation in adjuvant-induced arthritic （AIA） rats. Serum containing QTG was prepared and added to the osteoclasts, and activation of the tumor necrosis factor receptorassociated factor 6/mitogen-activated protein kinase/nuclear factor of activated T cells, cytoplasmic1 （TRAF6/ MAPK/NFATcl） pathways was examined. Results： The induced osteoclasts were multinucleated and stained positive for tartrate-resistant acid phosphatase （TRAP） staining. Serum containing QTG at 14.4, 7.2 or 3.6 g/kg inhibited the activation of TRAF6, extracellular regulated protein kinase （ERK）1/2, c-Jun N-terminal kinase （JNK） and p38 and decreased the percentage of cells with nuclear NFATcl in a dose-dependent manner, the high and middle doses exhibited clear inhibitory activity （P〈0.01 and P〈0.05, respectively）. After the addition of MAPK inhibitors, the NFATcl expression showed no significant difference compared with the control group （P〉0.05）. Conclusions： Serum containing QTG could generally inhibit the TRAF6/MAPK pathways and possibly inhibit the NFATcl pathway. In addition, QTG may regulate other signaling pathways that are related to osteoclast differentiation and maturation.
文摘Osteoclasts,which are derived from monocyte-macrophage precursors,are exclusive bone resorption cells.Limited evidence indicates that a class of small non-coding single-stranded RNAs known as“microRNAs”(miRNAs)is also involved in bone resorption.Although various miRNAs regulate cell proliferation and differentiation,few miRNAs have been reported to play a key role in the regulation of osteoclast differentiation.In this short review,the biology and functional mechanisms of miRNAs in osteoclastogenesis are summarized.The profiling,function,and target prediction of miRNAs are discussed as well.
基金supported by the National Natural Science Foundation of China (No.81972045)the Basic Applied Basic Research Foundation of Guangdong Province,China (No.2022A1515012373)the research fund from SUSTech Hospital.
文摘The pathogenic effects of type 2 diabetes on bone tissue are gaining attention,but the cellular and molecular mechanisms underlying osteoimmunology are still unclear in diabetes-related bone diseases.We delineated the single-cell transcriptome of bone marrow cells from both wide type and type 2 diabetes mice,which provided the first detailed global profile of bone marrow cells and revealed a distinct bone immune microenvironment at the genetic level under type 2 diabetic condition.It was observed that osteoclast activity was inhibited due to a dysre-gulated cytokine network,which ultimately led to decreased osteoclast formation and differen-tiation.In type 2 diabetes mice,a specific Cd36+cluster(cluster 18,monocytes/macrophages 2)was identified as the precursor of osteoclasts with diminished differentiation potential.AP-1 was demonstrated to be the key transcription factor in the underlying mechanism.
基金supported by the National Natural Science Foundation of China(Nos.11572209,11872260)National Natural Science Foundation of China(Key Program,No.11932014).
文摘To dissect which subset of bone marrow monocyte is the major precursor of osteoclast,3-month-old rat bone marrow was obtained for single-cell RNA sequencing.A total of 6091 cells were acquired for detailed analysis,with a median number of 1206 genes detected per cell and 17,959 genes detected in total.A total of 19 cell clusters were recognized,with the main lineages identified as B cells,Granulocytes,Monocytes,T cells,Erythrocytes and Macrophages.Monocytes were further divided into classical monocytes and non-classical monocytes.Compared with non-classical monocytes,classical monocytes highly expressed osteoclast differentiation related genes Mitf,Spi1,Fos and Csf1r.Additionally,biological processes of classical monocytes were related to osteoclast differentiation.qPCR revealed differentially expressed genes of classical monocytes played a role in osteoclast differentiation.In conclusion,classical monocytes were identified as the main precursors of osteoclasts in rats,and may contribute to osteoclast differentiation by regulating S100a4,S100a6,S100a10,Fn1,Vcan and Bcl2a1.The results of this study contribute to the understanding of the origin of osteoclasts and may provide potential biomarkers for early diagnosis of bone metabolic diseases,as well as molecular and cellular targets for clinical intervention in bone metabolic diseases.
基金supported in part by National Institutes of Health Grant HL-69458.
文摘Osteoclasts(OCs)are responsible for bone resorption in inflammatory joint diseases.Monocyte chemotactic protein-1(MCP-1)has been shown to induce differentiation of monocytes to OC precursors,but nothing is known about the underlying mechanisms.Here,we elucidate how MCPIP,induced by MCP-1,mediates this differentiation.Knockdown of MCPIP abolished MCP-1-mediated expression of OC markers,tartrate-resistant acid phosphatase,and serine protease cathepsin K.Expression of MCPIP induced p47PHOX and its membrane translocation,reactive oxygen species formation,and induction of endoplasmic reticulum(ER)stress chaperones,up-regulation of autophagy marker,Beclin-1,and lipidation of LC3,and induction of OC markers.Inhibition of oxidative stress attenuated ER stress and autophagy,and suppressed expression of OC markers.Inhibition of ER stress by a specific inhibitor or by knockdown of IRE1 blocked autophagy and induction of OC markers.ER stress inducers,tunicamycin and thapsigargin,induced expression of OC markers.Autophagy inhibition by 3′-methyladenine,LY294002,wortmannin or by knockdown of Beclin-1 or Atg 7 inhibited MCPIP-induced expression of OC markers.These results strongly suggest that MCP-1-induced differentiation of OC precursor cells is mediated via MCPIP-induced oxidative stress that causes ER stress leading to autophagy,revealing a novel mechanistic insight into the role of MCP-1 in OCs differentiation.
基金This work was supported by grants from the National Natural Science Foundation of China(81830078,81772347,and 81572123)Science and Technology Commission of Shanghai Municipality(19XD1434100 and 16430723500)+1 种基金Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(2016131A)Shanghai Jiao Tong University-The Chinese University of Hong Kong joint Research Collaboration Fund.
文摘PIP5k1βis crucial to the generation of phosphotidylinosotol(4,5)P2.PIP5k1βparticipates in numerous cellular activities,such as B cell and platelet activation,cell phagocytosis and endocytosis,cell apoptosis,and cytoskeletal organization.In the present work,we aimed to examine the function of PIP5k1βin osteoclastogenesis and osteogenesis to provide promising strategies for osteoporosis prevention and treatment.We discovered that PIP5k1β deletion in mice resulted in obvious bone loss and that PIP5k1β was highly expressed during both osteoclast and osteoblast differentiation.Deletion of the gene was found to enhance the proliferation and migration of bone marrow-derived macrophage-like cells to promote osteoclast differentiation.PIP5k1β-/-osteoclasts exhibited normal cytoskeleton architecture but stronger resorption activity.PIP5kip deficiency also promoted activation of mitogen-activated kinase and Akt signaling,enhanced TRAF6 and c-Fos expression,facilitated the expression and nuclear translocation of NFATC1,and upregulated Grb2 expression,thereby accelerating osteoclast differentiation and function.Finally,PIP5k1β enhanced osteoblast differentiation by upregulating master gene expression through triggering smad1/5/8 signaling.Therefore,PIP5k1βmodulates bone homeostasis and remodeling.
文摘Objective：To investigate the gene expression of osteoprotegerin（OPG） and osteoclast differentiation factor（ODF） in the bone tissue of patients with hip fracture due to osteoporosis. Methods：OPGmRNA and ODFmRNA in the bone tissue in 50 cases of osteoporosis sufferers（over 50 years old） with hip fracture（Observer Group） and 30 cases of hip facture sufferers with no osteoporosis（Control group） were analyzed with the Semi-Quantitative RT-PCR method. Results：The mRNA expressed of ODF, OPG were both high in the patients with hip fracture. In the control group, the expression of OPG mRNA was observed, while the expression of ODF mRNA was very slight. Conclusion：Aged patients contained all signals including OPG, ODF that are essential for inducing osteoclastogenesis and promoting bone resorption.
基金supported by the Hubei Province Health and Family Planning Scientific Research Foundation of China(No.WJ2015MB141)
文摘Osteoclast-like cells are known to inhibit arterial calcification. Receptor activator of NF-κB ligand（RANKL） is likely to act as an inducer of osteoclast-like cell differentiation. However,several studies have shown that RANKL promotes arterial calcification rather than inhibiting arterial calcification. The present study was conducted in order to investigate and elucidate this paradox. Firstly,RANKL was added into the media,and the monocyte precursor cells were cultured. Morphological observation and Tartrate resistant acid phosphatase（TRAP） staining were used to assess whether RANKL could induce the monocyte precursor cells to differentiate into osteoclast-like cells. During arterial calcification,in vivo and in vitro expression of RANKL and its inhibitor,osteoprotegerin（OPG）,was detected by real-time PCR. The extent of osteoclast-like cell differentiation was also assessed. It was found RANKL could induce osteoclast-like cell differentiation. There was no in vivo or in vitro expression of osteoclast-like cells in the early stage of calcification. At that time,the ratio of RANKL to OPG was very low. In the late stage of calcification,a small amount of osteoclast-like cell expression coincided with a relatively high ratio of RANKL to OPG. According to the results,the ratio of RANKL to OPG was very low during most of the arterial calcification period. This made it possible for OPG to completely inhibit RANKL-induced osteoclast-like cell differentiation. This likely explains why RANKL had the ability to induce osteoclast-like cell differentiation but acted as a promoter of calcification instead.
基金National Natural Science Foundation of China,Grant/Award Number:82173849Natural Science Foundation of Jiangsu Province,Grant/Award Number:BK20200097+1 种基金Priority Academic Program Development of Jiangsu Higher Education InstitutionsJiangsu Postgraduate Research and Practice Innovation Program,Grant/Award Numbers:KYCX21_1769,KYCX20_1451。
文摘Background:Multiple myeloma(MM)is the second most common hematological malignancy.An overwhelming majority of patients with MM progress to serious osteolytic bone disease.Aminoacyl-tRNA synthetase-interacting multifunctional protein 1(AIMP1)participates in several steps during cancer development and osteoclast differentiation.This study aimed to explore its role in MM.Methods:The gene expression profiling cohorts of MM were applied to determine the expression of AIMP1 and its association with MM patient prognosis.Enzyme-linked immunosorbent assay,immunohistochemistry,and Western blotting were used to detect AIMP1 expression.Protein chip analysis,RNA-sequencing,and chromatin immunoprecipitation and next-generation sequencing were employed to screen the interacting proteins and key downstream targets of AIMP1.The impact of AIMP1 on cellular proliferation was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay in vitro and a xenograft model in vivo.Bone lesions were evaluated using tartrate-resistant acid phosphatase staining in vitro.A NOD/SCID-TIBIA mouse model was used to evaluate the effect of siAIMP1-loaded exosomes on bone lesion formation in vivo.Results:AIMP1 expression was increased in MM patients and strongly associated with unfavorable outcomes.Increased AIMP1 expression promoted MM cell proliferation in vitro and in vivo via activation of the mitogen-activated protein kinase(MAPK)signaling pathway.Protein chip assays and subsequent experiments revealed that AIMP1 interacted with acidic leucine-rich nuclear phosphoprotein 32 family member A(ANP32A)to regulate histone H3 acetylation.In addition,AIMP1 increased histone H3 acetylation enrichment function of GRB2-associated and regulator of MAPK protein 2(GAREM2)to increase the phosphorylation of extracellular-regulated kinase 1/2(p-ERK1/2).Furthermore,AIMP1 promoted osteoclast differentiation by activating nuclear factor of activated T cells c1(NFATc1)in vitro.In contrast,exosome-coated small interfering RNA of AIMP1 effectively suppressed MM progression and osteoclast differentiation in vitro and in vivo.Conclusions:Our data demonstrate that AIMP1 is a novel regulator of histone H3 acetylation interacting with ANP32A in MM,which accelerates MM malignancy via activation of the MAPK signaling pathway.
基金Financial support was provided by the National Science Foundation of China(nos.21671099 and 91753121)the Shenzhen Basic Research Program(no.JCYJ20170413150538897)supported by the Fundamental Research Funds for the Central Universities(no.020514380139).
文摘Black phosphorus(BP)is a newly discovered two-dimensional material that has promising applications from bioelectronics to biomedicine.However,facile oxidation of BP leads to changes in surface chemical composition and physical properties,often being referred to as the degradation process of BP.Degradation products of BP nanosheets,namely,oxidized BP nanosheets(oBPNSs),are routinely considered as by-products without many uses.Herein,we found that oBPNSs displayed excellent osteoclastogenesis inhibition effects without impairing cell viability.In contrast to the classic antiresorptive bisphosphonate drugs,oBPNSs showed a different mode of action by suppressing the maturation of osteoclasts.Bone resorption assays,osteoclast actin ring analysis,and tartrate-resistant acid phosphate activity assay results indicated that oBPNSs suppressed receptor activator of nuclear factor-κB(NF-κB)ligand(RANKL)-induced osteoclastogenesis in a dose-and oxidation-dependent manner.Transcriptomic and proteomic analyses indicated that oBPNSs inhibited the activation of the NF-κB signaling pathway and phosphorylation of mitogen-activated protein kinase(MAPK)in differentiated osteoclasts,as confirmed by Western blot analysis.Our results suggest that oBPNSs might be potential antiresorptive nanomaterials to treat osteoporosis.
