Objectives Dysregulated osteoclast function contributes to skeletal diseases.However,the specific ubiquitination regulators of the osteoclastogenesis repressor MafB,particularly at the post-translational level,remain ...Objectives Dysregulated osteoclast function contributes to skeletal diseases.However,the specific ubiquitination regulators of the osteoclastogenesis repressor MafB,particularly at the post-translational level,remain undefined.This study aims to identify ubiquitin-specific proteases(USPs)that deubiquitinate MafB and enhance its stability.Methods We constructed a MafB-conjugated luciferase and overexpressed 40 individual USPs,measuring changes in luciferase activity.The identified USP was overexpressed in human CD14^(+) peripheral blood mononuclear cells(PBMCs)to evaluate its effect.Osteoclast differentiation was assessed through osteoclast marker Integrin alpha-V(CD51)staining and Western blot analysis.Co-immunoprecipitation(co-IP)was performed to assess the interplay.The influence on MafB ubiquitination and degradation was evaluated via immunoprecipitation and Western blot.Finally,MafB was knocked down in the USP-overexpressing PBMCs to analyze its effect on osteoclast differentiation.Results Overexpression of ubiquitin-specific protease 29(USP29)significantly increased MafB expression by approximately 75%(p<0.0001).Elevated USP29 levels strongly inhibited osteoclastic differentiation in CD14^(+) PBMCs(p<0.0001).USP29 was found to interact with MafB,markedly reducing its ubiquitination and subsequent degradation in PBMCs(p<0.001).Knocking down MafB in USP29-overexpressing PBMCs alleviated the inhibitory effect of USP29 on osteoclastogenesis.Conclusion USP29 acts as a potent stabilizer of MafB,inhibiting osteoclastogenesis in human CD14^(+) PBMCs,at least in part,by enhancing MafB stability.These findings expand our understanding of USP29’s role and the post-translational regulation of MafB.Furthermore,USP29 serves as a vital factor that controls osteoclast differentiation,and its regulatory function is at least partially mediated by deubiquitinating and stabilizing MafB.展开更多
Giant cell tumors of the pancreas come in three varieties-osteoclastic,pleomorphic,and mixed histology.These tumors have distinctive endoscopic,clinical,and cytological features.Giant cell tumors have a controversial ...Giant cell tumors of the pancreas come in three varieties-osteoclastic,pleomorphic,and mixed histology.These tumors have distinctive endoscopic,clinical,and cytological features.Giant cell tumors have a controversial histogenesis,with some authors favoring an epithelial origin and others favoring a mesenchymal origin.The true origin of these lesions remains unclear at this time.These are also very rare tumors but proper identification and differentiation from more common pancreatic adenocarcinoma is important.The risk factors of these tumors and the prognosis may be different from those associated with standard pancreatic adenocarcinoma.Recognition of these differences can significantly affect patient care.These lesions have a unique appearance when imaged with endoscopic ultrasound(EUS),and these lesions can be diagnosed via EUS guided Fine Needle Aspiration(FNA).This manuscript will review the endoscopic,clinical,and pathologic features of these tumors.展开更多
Toll-like receptors(TLRs)play pivotal roles in inflammation and provide important links between the immune and skeletal systems.Although the activation of TLRs may affect osteoclast differentiation and bone metabolism...Toll-like receptors(TLRs)play pivotal roles in inflammation and provide important links between the immune and skeletal systems.Although the activation of TLRs may affect osteoclast differentiation and bone metabolism,whether and how TLRs are required for normal bone remodeling remains to be fully explored.In the current study,we show for the first time that TLR9^(-/-)mice exhibit a low bone mass and low-grade systemic chronic inflammation,which is characterized by the expansion of CD4^(+)T cells and increased levels of inflammatory cytokines,including TNFα,RANKL,and IL1β.The increased levels of these cytokines significantly promote osteoclastogenesis and induce bone loss.Importantly,TLR9 deletion alters the gut microbiota,and this dysbiosis is the basis of the systemic inflammation and bone loss observed in TLR9^(-/-)mice.Furthermore,through single-cell RNA sequencing,we identified myeloid-biased hematopoiesis in the bone marrow of TLR9^(-/-)mice and determined that the increase in myelopoiesis,likely caused by the adaptation of hematopoietic stem cells to systemic inflammation,also contributes to inflammation-induced osteoclastogenesis and subsequent bone loss in TLR9^(-/-)mice.Thus,our study provides novel evidence that TLR9 signaling connects the gut microbiota,immune system,and bone and is critical in maintaining the homeostasis of inflammation,hematopoiesis,and bone metabolism under normal conditions.展开更多
Osteoporosis bone defect is a refractory orthopaedic disease which characterized by impaired bone quality and bone regeneration capacity.Current therapies,including antiosteoporosis drugs and artificial bone grafts,ar...Osteoporosis bone defect is a refractory orthopaedic disease which characterized by impaired bone quality and bone regeneration capacity.Current therapies,including antiosteoporosis drugs and artificial bone grafts,are not always satisfactory.Herein,a strontium-substituted calcium phosphate silicate bioactive ceramic(Sr-CPS)was fabricated.In the present study,the extracts of Sr-CPS were prepared for in vitro study and Sr-CPS scaffolds were used for in vivo study.The cytocompatibility,osteogenic and osteoclastogenic properties of Sr-CPS extracts were characterized in comparison to CPS.Molecular mechanisms were also evaluated by Western blot.Sr-CPS extracts were found to promote osteogenesis by upregulating Wnt/β-catenin signal pathways and inhibit osteoclastogenesis through downregulating NF-κB signal pathway.In vivo,micro-CT,histological and histomorphometric observation were conducted after 8 weeks of implantation to evaluate the bone formation using calvarial defects model in ovariectomized rats.Compared with CPS,Sr-CPS significantly promoted critical sized ovariectomy(OVX)calvarial defects healing.Among all the samples,Sr-10 showed the best performance due to a perfect match of bone formation and scaffold degradation rates.Overall,the present study demonstrated that Sr-CPS ceramic can dually modulate both bone formation and resorption,which might be a promising candidate for the reconstruction of osteoporotic bone defect.展开更多
β-Tricalcium Phosphate(β-TCP),one of the most used bone graft substitutes,may contain up to 5 wt%foreign phase according to standards.Typical foreign phases includeβ-calcium pyrophosphate(β-CPP)and hydroxyapatite(...β-Tricalcium Phosphate(β-TCP),one of the most used bone graft substitutes,may contain up to 5 wt%foreign phase according to standards.Typical foreign phases includeβ-calcium pyrophosphate(β-CPP)and hydroxyapatite(HA).Currently,the effect of small amounts of impurities on β-TCP resorption is unknown.This is surprising since pyrophosphate is a very potent osteoclast inhibitor.The main aim of this study was to assess the effect of small β-CPP fractions(<1 wt%)on the in vitro osteoclastic resorption of β-TCP.A minor aim was to examine the effect of β-CPP and HA impurities on the physico-chemical properties of β-TCP powders and sintered cylinders.Twenty-six batches of β-TCP powder were produced with a Ca/P molar ratio varying between 1.440 and 1.550.Fifteen were further processed to obtain dense and polished β-TCP cylinders.Finally,six of them,with a Ca/P molar ratio varying between 1.496(1 wt% β-CPP)and 1.502(1 wt% HA),were incubated in the presence of osteoclasts.Resorption was quantified by white-light interferometry.Osteoclastic resorption was significantly inhibited by β-CPP fraction in a linear manner.The presence of 1% β-CPP reduced β-TCP resorption by 40%,which underlines the importance of controllingβ-CPP content when assessing β-TCP biological performance.展开更多
Osteoclasts are essential for maintaining healthy bone.Pathological elevation of os-teoclastogenesis or osteoclast activity can cause osteoporosis and increase the risk of bone fracture.However,a few options are avail...Osteoclasts are essential for maintaining healthy bone.Pathological elevation of os-teoclastogenesis or osteoclast activity can cause osteoporosis and increase the risk of bone fracture.However,a few options are available for directly measuring osteoclast activity in vivo to test interventions that may affect osteoclasts.Here,we describe an in vivo method to measure osteoclast-mediated bone loss targeted at normal mouse calvaria.The method employs a novel procedure for measuring osteoclast resorption pits using micro-computed tomography.The potential utility of this mouse calvaria model to assess therapies targeting osteoclasts was validated using zoledronic acid,which is a nitrogen-containing bisphosphonate drug used to treat osteoporosis.展开更多
Bone is highly innervated,and its regeneration is significantly nerve-dependent.Extensive evidence suggests that the nervous system plays an active role in bone metabolism and development by modulating osteoblast and ...Bone is highly innervated,and its regeneration is significantly nerve-dependent.Extensive evidence suggests that the nervous system plays an active role in bone metabolism and development by modulating osteoblast and osteoclast activity.However,the majority of research to date has focused on the direct effects of peripheral nerves and their neurotransmitters on bone regeneration.Emerging studies have begun to reveal a more intricate role of nerves in regulating the immune microenvironment,which is crucial for bone regeneration.This review summarizes how nerves influence bone regeneration through modulation of the immune microenvironment.We first discuss the changes in peripheral nerves during the regenerative process.We then describe conduction and paracrine pathways through which nerves affect the osteogenic immune microenvironment,emphasizing nerves,neural factors,and their impacts.Our goal is to deepen the understanding of the nerve-immune axis in bone regeneration.A better grasp of how nerves influence the osteogenic immune microenvironment may lead to new strategies that integrate the nervous,immune,and skeletal systems to promote bone regeneration.展开更多
Estrogen deficiency after menopause accelerates bone loss by stimulating osteoclast formation and activity,but the molecular pathways that link estrogen signaling to osteoclast regulation remain incompletely defined.H...Estrogen deficiency after menopause accelerates bone loss by stimulating osteoclast formation and activity,but the molecular pathways that link estrogen signaling to osteoclast regulation remain incompletely defined.Here,we identify the sialyltransferase ST3GAL-I as a key mediator of RANKL-induced osteoclastogenesis.RANKL activates c-FOS to drive ST3GAL1 transcription,whereas estrogen-bound ERαcompetes with TRAF6 and suppresses this c-FOS–dependent induction.In a clinical cohort of pre-menopausal and post-menopausal women with or without osteoporosis,serum total andα-2,3-linked sialic acid levels increased with age and were highest in post-menopausal osteoporotic patients.Single-cell RNA sequencing of human bone revealed that osteoclasts form a prominent cluster only after menopause,where FOS,CTSK,and ST3GAL1 are strongly co-expressed,and the estrogen-responsive gene PGR is down-regulated.Additionally,in vivo experiments showed that sialidase treatment in estrogen-deficient models effectively reduced osteoclast-mediated bone loss,mimicking the effects of estradiol.These findings define a direct molecular link between loss of estrogen and activation of a FOS–ST3GAL1 sialylation pathway in osteoclasts,providing mechanistic insight into the enhanced bone resorption characteristic of post-menopausal osteoporosis.展开更多
The normal growth and development of the skull is a tightly regulated process that occurs along the osteogenic interfaces of the cranial sutures.Here,the borders of the calvarial bones and neighboring tissues above an...The normal growth and development of the skull is a tightly regulated process that occurs along the osteogenic interfaces of the cranial sutures.Here,the borders of the calvarial bones and neighboring tissues above and below,function as a complex.Through coordinated remodeling efforts of bone deposition and resorption,the cranial sutures maintain a state of patency from infancy through early adulthood as the skull continues to grow and accommodate the developing brain’s demands for expansion.However,when this delicate balance is disturbed,a number of pathologic conditions ensue;and if left uncorrected,may result in visual and neurocognitive impairments.A prime example includes craniosynostosis,or premature fusion of one or more cranial and/or facial suture(s).At the present time,the only therapeutic measure for craniosynostosis is surgical correction by cranial vault reconstruction.However,elegant studies performed over the past decade have identified several genes critical for the maintenance of suture patency and induction of suture fusion.Such deeper understandings of the pathogenesis and molecular mechanisms that regulate suture biology may provide necessary insights toward the development of non-surgical therapeutic alternatives for patients with cranial suture defects.In this review,we discuss the intricate cellular and molecular interplay that exists within the suture among its three major components:dura mater,osteoblastic related molecular pathways and osteoclastic related molecular pathways.展开更多
Background Dehydroepiandrosterone （DHEA） is widely known for its beneficial effect on postmenopausal osteoporosis, although the underlying mechanisms remain mainly unclear. In this study, we tried to determine the a...Background Dehydroepiandrosterone （DHEA） is widely known for its beneficial effect on postmenopausal osteoporosis, although the underlying mechanisms remain mainly unclear. In this study, we tried to determine the activation of mitogen-activated protein kinase signal pathways during DHEA treatment and the indirect role of osteoblasts （OBs） on osteoclasts under the DHEA treatment of postmenopausal osteoporosis. Methods Primary human OBs and osteoclast-like cells were cultured and, we pretreated OBs with or without U0126 （a highly selective inhibitor of both MEK1 and MEK2）. The OBs were treated with DHEA. We then tested the effects of DHEA on human osteoblastic viability, osteoprotegerin production and the expression of phosphor-ERK1/2 （extracellular signal-regulated kinase）. In the presence or absence of OBs, the function of osteoclastic resorption upon DHEA treatment was calculated. Results DHEA promoted the human osteoblastic proliferation and inhibited the osteoblastic apoptosis within the concentration range of 108-106 mol/L （P 〈0.05, P 〈0.01, respectively）. Within the effective concentration range, the expression of phosphor-ERK1/2 and osteoprotegerin was increased by DHEA and blocked by U0126. In the presence of OBs, DHEA could significantly decrease the number and the area of bone resorption lacuna （P 〈0.05 and P 〈0.01, respectively）. Without OBs, however, the effects of DHEA on the bone resorption lacuna were almost completely abolished. Conclusions DHEA could indirectly inhibit the human osteoclastic resorption through promoting the osteoblastic viability and osteoprotegerin production, which is mediated by mitogen-activated protein kinases signal pathway involving the phosphor-ERK1/2.展开更多
Itaconate,a macrophage-specific anti-inflammatory metabolite,has recently emerged as a critical regulator in rheumatoid arthritis pathogenesis.We found that itaconate is a TNF-αresponsive metabolite significantly ele...Itaconate,a macrophage-specific anti-inflammatory metabolite,has recently emerged as a critical regulator in rheumatoid arthritis pathogenesis.We found that itaconate is a TNF-αresponsive metabolite significantly elevated in the serum and synovial fluid of rheumatoid arthritis patients and we demonstrated that itaconate is primarily produced by inflammatory macrophages rather than osteoclasts or osteoblasts.In TNF-transgenic and Irg1−/−hybrid mice,a more severe bone destruction phenotype was observed.展开更多
This study investigated the regulatory potential of salidroside(SAL),a primary active compound in Rhodiola rosea L.,on osteoclast differentiation by modulating the hypoxia-inducible factor 1-alpha(HIF-1α)pathway in o...This study investigated the regulatory potential of salidroside(SAL),a primary active compound in Rhodiola rosea L.,on osteoclast differentiation by modulating the hypoxia-inducible factor 1-alpha(HIF-1α)pathway in osteoblasts.Luciferase reporter assay and chromatin immunoprecipitation(Ch IP)assay were employed to validate whether the receptor activator of nuclear factor-κB ligand(RANKL)is the downstream target gene of HIF-1αin osteoblasts.The study also utilized lipopolysaccharide(LPS)-induced mouse osteolysis to examine the impact of SAL on osteolysis in vivo.Furthermore,conditioned medium(CM)from SAL-pretreated osteoblasts was used to investigate the paracrine effects on osteoclastogenesis through the HIF-1αpathway.Hypoxic condition-induced overexpression of HIF-1αupregulated RANKL levels by binding to the RANKL promoter and enhancing transcription in osteoblastic cells.In vivo,SAL significantly alleviated bone tissue hypoxia and decreased the expression of HIF-1αby downregulating the expression of RANKL,vascular endothelial growth factor(VEGF),interleukin 6(IL-6),and angiopoietin-like 4(ANGPTL4).In the paracrine experiment,conditioned media from SAL-pretreated osteoblasts inhibited differentiation through the HIF-1α/RANKL,VEGF,IL-6,and ANGPTL4 pathways.RANKL emerges as the downstream target gene regulated by HIF-1αin osteoblasts.SAL significantly alleviates bone tissue hypoxia and bone loss in LPS-induced osteolysis through the HIF-1α/RANKL,VEGF,IL-6,and ANGPTL4 pathways.SAL inhibits osteoclast differentiation by regulating osteoblast paracrine secretion.展开更多
Osteoporosis is a prevalent skeletal condition characterized by reduced bone mass and strength,leading to increased fragility.Buqi-Tongluo(BQTL)decoction,a traditional Chinese medicine(TCM)prescription,has yet to be f...Osteoporosis is a prevalent skeletal condition characterized by reduced bone mass and strength,leading to increased fragility.Buqi-Tongluo(BQTL)decoction,a traditional Chinese medicine(TCM)prescription,has yet to be fully evaluated for its potential in treating bone diseases such as osteoporosis.To investigate the mechanism by which BQTL decoction inhibits osteoclast differentiation in vitro and validate these findings through in vivo experiments.We employed MTS assays to assess the potential proliferative or toxic effects of BQTL on bone marrow macrophages(BMMs)at various concentrations.TRAc P experiments were conducted to examine BQTL's impact on osteoclast differentiation.RT-PCR and Western blot analyses were utilized to evaluate the relative expression levels of osteoclast-specific genes and proteins under BQTL stimulation.Finally,in vivo experiments were performed using an osteoporosis model to further validate the in vitro findings.This study revealed that BQTL suppressed receptor activator of NF-κB ligand(RANKL)-induced osteoclastogenesis and osteoclast resorption activity in vitro in a dose-dependent manner without observable cytotoxicity.The inhibitory effects of BQTL on osteoclast formation and function were attributed to the downregulation of NFATc1 and c-fos activity,primarily through attenuation of the MAPK,NF-κB,and Calcineurin signaling pathways.BQTL's inhibitory capacity was further examined in vivo using an ovariectomized(OVX)rat model,demonstrating a strong protective effect against bone loss.BQTL may serve as an effective therapeutic TCM for the treatment of postmenopausal osteoporosis and the alleviation of bone loss induced by estrogen deficiency and related conditions.展开更多
Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19...Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19 is important for its function in osteoclast differentiation,and LEL-Fc,a competitive inhibitor of Tm4sf19,effectively suppresses osteoclast multinucleation and prevent bone loss associated with osteoporosis.This study aimed to investigate the role of Tm4sf19 in RA,an inflammatory and abnormal osteoclast disease,using a mouse model of collagen-induced arthritis(CIA).Tm4sf19 expression was observed in macrophages and osteoclasts within the inflamed synovium,and Tm4sf19 expression was increased together with inflammatory genes in the joint bones of CIA-induced mice compared with the sham control group.Inhibition of Tm4sf19 by LEL-Fc demonstrated both preventive and therapeutic effects in a CIA mouse model,reducing the CIA score,swelling,inflammation,cartilage damage,and bone damage.Knockout of Tm4sf19 gene or inhibition of Tm4sf19 activity by LEL-Fc suppressed LPS/IFN-γ-induced TLR4-mediated inflammatory signaling in macrophages.LEL-Fc disrupted not only the interaction between Tm4sf19 and TLR4/MD2,but also the interaction between TLR4 and MD2.μCT analysis showed that LEL-Fc treatment significantly reduced joint bone destruction and bone loss caused by hyperactivated osteoclasts in CIA mice.Taken together,these findings suggest that LELFc may be a potential treatment for RA and RA-induced osteoporosis by simultaneously targeting joint inflammation and bone destruction caused by abnormal osteoclast activation.展开更多
Ankylosing spondylitis(AS)is a chronic,progressive,systemic autoimmune disease characterised by spinal stiffness and ocular,cardiac,intestinal,and peripheral joint involvements.Genetics,infectious agents,and immune-me...Ankylosing spondylitis(AS)is a chronic,progressive,systemic autoimmune disease characterised by spinal stiffness and ocular,cardiac,intestinal,and peripheral joint involvements.Genetics,infectious agents,and immune-mediated inflammatory processes have all been hypothesized to contribute to AS pathogenesis,but the precise aetiology remains elusive.Recent studies have identified biological and cellular factors that correlate with the onset and progression of AS.This has provided avenues of research that may help elucidate disease mechanisms and lead to advances in therapeutic interventions.This study aimed to examine some of the findings from recent molecular studies,focusing on the molecular mechanism and associated factors such as interleukin-17,tumor necrosis factor-alpha,receptor activator of nuclear factor-kappa B/receptor activator of nuclear factor-kappa B ligand/osteoprotegerin pathway,and related micro-RNAs to gain insight into aberrant bone formation in AS and potential approaches to its prevention.This editorial also addresses the contribution of osteoclasts to bone pathology in AS.The author examined the molecular pathways governing osteoclast differentiation and activity,with particular emphasis on relevant cytokines and immune cell interactions.A comprehensive understanding of these mechanisms is essential for the development of targeted therapies to mitigate excessive bone resorption and pathological skeletal remodeling in AS.展开更多
Polyetheretherketone(PEEK)is a desirable candidate to replace conventional metal implants owing to its excellent mechanical properties.However,the intrinsic bioinertness of PEEK results in inferior or delayed osseoint...Polyetheretherketone(PEEK)is a desirable candidate to replace conventional metal implants owing to its excellent mechanical properties.However,the intrinsic bioinertness of PEEK results in inferior or delayed osseointegration,which limits its further clinical application.To address these challenges,one leading strategy is to construct a biofunctionalized surface on PEEK that provides a coordinated osteoblastosteoclast interactions microenvironment.Herein,alendronate(ALN),a common bone absorption inhibitor,was loaded in biomedical inorganic/organic microspheres,consisting of bioactive inorganic nanohydroxyapatite core,and chitosan(CS)shell.Polydopamine(PDA)modification was employed to ensure the adherence of the microspheres to the PEEK surface.The delivery of ALN and Ca^(2+)from these microspheres simultaneously suppressed osteoclastogenesis and promoted osteogenesis,resulting in a coordinated cascade of osteoblast-osteoclast interactions crucial for the per-implant osseointegration.In vitro experiments demonstrated that the PEEK surface exhibited satisfactory biocompatibility and enhanced the proliferation and osteogenic differentiation of rat bone mesenchymal stem cells while inhibiting the osteoclast differentiation.Moreover,the in vivo rat femoral drilling model demonstrated superior osseointegration three months after implantation.By considering the bone remodeling processes,this study proposes a novel biofunctionalized PEEK surface that regulates the activities of both osteoblasts and osteoclasts to promote osseointegration.展开更多
Abnormal activation of macrophages and osteoclasts(OCs)contributes significantly to rheumatoid arthritis(RA)development by secretion of numerous inflammatory factors.Notably,these cells exhibit significant upregulatio...Abnormal activation of macrophages and osteoclasts(OCs)contributes significantly to rheumatoid arthritis(RA)development by secretion of numerous inflammatory factors.Notably,these cells exhibit significant upregulation of folate receptor proteins on their surfaces.Unfortunately,there is a current lack of safe and effective therapeutic drugs for RA.Xuetongsu(XTS),a triterpenoid compound extracted fromKadsura heteroclita Roxb Craib,has demonstrated the ability to significantly inhibit the proliferation of RA fibroblast-like synoviocytes(RAFLS).However,its clinical application is hampered by poor targeting and short half-life.To address these drawbacks,we previously developed a nano-drug system named HRPS nanoparticles(NPs),which effectively targets RAFLS and inhibits synovial hyperplasia.However,this system overlooked the essential role of OCs in RA-related bone destruction.Therefore,we designed a novel folate-modified biomimetic Prussian blue(PB)-XTS NP(FMPX NP)for the selective delivery of XTS into inflammatory macrophages and OCs.The NP exhibits an excellent photothermal effect when assisted by laser irradiation,facilitating targeted release of XTS within inflammatory macrophages and OCs.The synergistic anti-inflammatory and reactive oxygen species scavenging effects of PB NPs and XTS are mediated by the inhibition of the NF-κB signaling pathway in inflammatory macrophages and RANK/RANKL/NFATc1 signaling pathway in OCs.In vivo experiments showed that FMPX NPs extended the half-life of XTS by 2.32 times,decreased hind foot swelling from 12.10±0.49 mm to 8.24±0.09 mm in the model group,and prevented bone damage.In conclusion,this study introduces a novel dual-targeted nano-based therapy for RA joints and highlights its potential for biochemical photothermal triple therapy for RA.FMPX NPs inhibit arthritis-related inflammation and bone destruction through a dual-target strategy,providing new insights for targeted drug therapies in clinical RA treatment.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
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
Rheumatoid arthritis(RA)is a progressive autoimmune disease characterized by bone destruction that is primarily caused by the overactivation of osteoclasts(OCs),which are critical therapeutic targets.Triptolide(TP)has...Rheumatoid arthritis(RA)is a progressive autoimmune disease characterized by bone destruction that is primarily caused by the overactivation of osteoclasts(OCs),which are critical therapeutic targets.Triptolide(TP)has strong anti-RA effects but is limited by its narrow therapeutic window and associated toxicity,necessitating combination therapy to increase its efficacy and reduce side effects.Medicarpin(Med),a flavonoid with anti-inflammatory and anti-bone destruction properties,has shown potential in reducing osteoclastogenesis.However,the mechanisms underlying the synergistic effects of TP and Med on RA treatment remain unclear.We addressed this issue by evaluating the effects of TP,Med,and their combination on a collagen-induced arthritis(CIA)rat model,with a focus on bone erosion as the primary research endpoint.We subsequently performed experimental validation in an in vitro OC dif-ferentiation model to assess the impacts of these treatments on OC formation and function.Based on polymerase chain reaction(PCR)microarray data from RA patients,further investigations focused on N^(6)-methyladenosine(m^(6)A)methylation and its regulatory factors,methyltransferase-like 3(METTL3)and YT521-B homology domain family protein 1(YTHDF1),which have been identified as potential tar-gets of TP and Med.Key findings revealed that the TP and Med combination significantly alleviated bone destruction and inhibited OC differentiation,exerting stronger effects at lower doses than either drug alone.Mechanistically,TP and Med synergistically modulated METTL3 and YTHDF1 to suppress osteo-clastogenesis through distinct m6 A methylation pathways,contributing to the mitigation of RA-associated bone destruction.Overall,our data highlight the potential of the m^(6)A modification as a ther-apeutic mechanism for the combined use of TP and Med for RA treatment,providing a theoretical basis for the clinical application of herbal active ingredient combinations.展开更多
文摘Objectives Dysregulated osteoclast function contributes to skeletal diseases.However,the specific ubiquitination regulators of the osteoclastogenesis repressor MafB,particularly at the post-translational level,remain undefined.This study aims to identify ubiquitin-specific proteases(USPs)that deubiquitinate MafB and enhance its stability.Methods We constructed a MafB-conjugated luciferase and overexpressed 40 individual USPs,measuring changes in luciferase activity.The identified USP was overexpressed in human CD14^(+) peripheral blood mononuclear cells(PBMCs)to evaluate its effect.Osteoclast differentiation was assessed through osteoclast marker Integrin alpha-V(CD51)staining and Western blot analysis.Co-immunoprecipitation(co-IP)was performed to assess the interplay.The influence on MafB ubiquitination and degradation was evaluated via immunoprecipitation and Western blot.Finally,MafB was knocked down in the USP-overexpressing PBMCs to analyze its effect on osteoclast differentiation.Results Overexpression of ubiquitin-specific protease 29(USP29)significantly increased MafB expression by approximately 75%(p<0.0001).Elevated USP29 levels strongly inhibited osteoclastic differentiation in CD14^(+) PBMCs(p<0.0001).USP29 was found to interact with MafB,markedly reducing its ubiquitination and subsequent degradation in PBMCs(p<0.001).Knocking down MafB in USP29-overexpressing PBMCs alleviated the inhibitory effect of USP29 on osteoclastogenesis.Conclusion USP29 acts as a potent stabilizer of MafB,inhibiting osteoclastogenesis in human CD14^(+) PBMCs,at least in part,by enhancing MafB stability.These findings expand our understanding of USP29’s role and the post-translational regulation of MafB.Furthermore,USP29 serves as a vital factor that controls osteoclast differentiation,and its regulatory function is at least partially mediated by deubiquitinating and stabilizing MafB.
文摘Giant cell tumors of the pancreas come in three varieties-osteoclastic,pleomorphic,and mixed histology.These tumors have distinctive endoscopic,clinical,and cytological features.Giant cell tumors have a controversial histogenesis,with some authors favoring an epithelial origin and others favoring a mesenchymal origin.The true origin of these lesions remains unclear at this time.These are also very rare tumors but proper identification and differentiation from more common pancreatic adenocarcinoma is important.The risk factors of these tumors and the prognosis may be different from those associated with standard pancreatic adenocarcinoma.Recognition of these differences can significantly affect patient care.These lesions have a unique appearance when imaged with endoscopic ultrasound(EUS),and these lesions can be diagnosed via EUS guided Fine Needle Aspiration(FNA).This manuscript will review the endoscopic,clinical,and pathologic features of these tumors.
基金supported by grants from the National Natural Science Foundation of China(nos.81820100820 and 81372845 to C.Z.,no.81400855 to C.Y.and no.82170893 to Q.T.)supported by National Key R&D Program of China grant no.2018YFC1106300(to C.Z.)+1 种基金Natural Science Foundation of Shanghai grant no.21ZR1448600(to C.Y.)Science and Technology Commission of Shanghai Municipality grant no.14pj1407200(to C.Y.)。
文摘Toll-like receptors(TLRs)play pivotal roles in inflammation and provide important links between the immune and skeletal systems.Although the activation of TLRs may affect osteoclast differentiation and bone metabolism,whether and how TLRs are required for normal bone remodeling remains to be fully explored.In the current study,we show for the first time that TLR9^(-/-)mice exhibit a low bone mass and low-grade systemic chronic inflammation,which is characterized by the expansion of CD4^(+)T cells and increased levels of inflammatory cytokines,including TNFα,RANKL,and IL1β.The increased levels of these cytokines significantly promote osteoclastogenesis and induce bone loss.Importantly,TLR9 deletion alters the gut microbiota,and this dysbiosis is the basis of the systemic inflammation and bone loss observed in TLR9^(-/-)mice.Furthermore,through single-cell RNA sequencing,we identified myeloid-biased hematopoiesis in the bone marrow of TLR9^(-/-)mice and determined that the increase in myelopoiesis,likely caused by the adaptation of hematopoietic stem cells to systemic inflammation,also contributes to inflammation-induced osteoclastogenesis and subsequent bone loss in TLR9^(-/-)mice.Thus,our study provides novel evidence that TLR9 signaling connects the gut microbiota,immune system,and bone and is critical in maintaining the homeostasis of inflammation,hematopoiesis,and bone metabolism under normal conditions.
基金financial support from National Key Research and Development Program of China(Grant No.2018YFC2002303)National Natural Science Foundation of China(Grant No.51672304)International Partnership Program of Chinese Academy of Science(Grant No.GJHZ1760).
文摘Osteoporosis bone defect is a refractory orthopaedic disease which characterized by impaired bone quality and bone regeneration capacity.Current therapies,including antiosteoporosis drugs and artificial bone grafts,are not always satisfactory.Herein,a strontium-substituted calcium phosphate silicate bioactive ceramic(Sr-CPS)was fabricated.In the present study,the extracts of Sr-CPS were prepared for in vitro study and Sr-CPS scaffolds were used for in vivo study.The cytocompatibility,osteogenic and osteoclastogenic properties of Sr-CPS extracts were characterized in comparison to CPS.Molecular mechanisms were also evaluated by Western blot.Sr-CPS extracts were found to promote osteogenesis by upregulating Wnt/β-catenin signal pathways and inhibit osteoclastogenesis through downregulating NF-κB signal pathway.In vivo,micro-CT,histological and histomorphometric observation were conducted after 8 weeks of implantation to evaluate the bone formation using calvarial defects model in ovariectomized rats.Compared with CPS,Sr-CPS significantly promoted critical sized ovariectomy(OVX)calvarial defects healing.Among all the samples,Sr-10 showed the best performance due to a perfect match of bone formation and scaffold degradation rates.Overall,the present study demonstrated that Sr-CPS ceramic can dually modulate both bone formation and resorption,which might be a promising candidate for the reconstruction of osteoporotic bone defect.
基金the Swiss National Science Foundation for its funding(Grant no.200021_169027).
文摘β-Tricalcium Phosphate(β-TCP),one of the most used bone graft substitutes,may contain up to 5 wt%foreign phase according to standards.Typical foreign phases includeβ-calcium pyrophosphate(β-CPP)and hydroxyapatite(HA).Currently,the effect of small amounts of impurities on β-TCP resorption is unknown.This is surprising since pyrophosphate is a very potent osteoclast inhibitor.The main aim of this study was to assess the effect of small β-CPP fractions(<1 wt%)on the in vitro osteoclastic resorption of β-TCP.A minor aim was to examine the effect of β-CPP and HA impurities on the physico-chemical properties of β-TCP powders and sintered cylinders.Twenty-six batches of β-TCP powder were produced with a Ca/P molar ratio varying between 1.440 and 1.550.Fifteen were further processed to obtain dense and polished β-TCP cylinders.Finally,six of them,with a Ca/P molar ratio varying between 1.496(1 wt% β-CPP)and 1.502(1 wt% HA),were incubated in the presence of osteoclasts.Resorption was quantified by white-light interferometry.Osteoclastic resorption was significantly inhibited by β-CPP fraction in a linear manner.The presence of 1% β-CPP reduced β-TCP resorption by 40%,which underlines the importance of controllingβ-CPP content when assessing β-TCP biological performance.
基金National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health,Grant/Award Number:R01AR069044Rutgers-New Jersey Medical School Department of Orthopaedics。
文摘Osteoclasts are essential for maintaining healthy bone.Pathological elevation of os-teoclastogenesis or osteoclast activity can cause osteoporosis and increase the risk of bone fracture.However,a few options are available for directly measuring osteoclast activity in vivo to test interventions that may affect osteoclasts.Here,we describe an in vivo method to measure osteoclast-mediated bone loss targeted at normal mouse calvaria.The method employs a novel procedure for measuring osteoclast resorption pits using micro-computed tomography.The potential utility of this mouse calvaria model to assess therapies targeting osteoclasts was validated using zoledronic acid,which is a nitrogen-containing bisphosphonate drug used to treat osteoporosis.
基金supported by grants from the National Natural Science Foundation of China(No.82372382,82002333,32371412,32071349)the Central Guidance on Local Science and Technology Development Fund of Zhejiang Province(No.2024ZY01033)+1 种基金the Zhejiang Provincial Natural Science Foundation of China(No.LY24C100001)the Key Research and Development Program of Zhejiang(No.2022C01076)。
文摘Bone is highly innervated,and its regeneration is significantly nerve-dependent.Extensive evidence suggests that the nervous system plays an active role in bone metabolism and development by modulating osteoblast and osteoclast activity.However,the majority of research to date has focused on the direct effects of peripheral nerves and their neurotransmitters on bone regeneration.Emerging studies have begun to reveal a more intricate role of nerves in regulating the immune microenvironment,which is crucial for bone regeneration.This review summarizes how nerves influence bone regeneration through modulation of the immune microenvironment.We first discuss the changes in peripheral nerves during the regenerative process.We then describe conduction and paracrine pathways through which nerves affect the osteogenic immune microenvironment,emphasizing nerves,neural factors,and their impacts.Our goal is to deepen the understanding of the nerve-immune axis in bone regeneration.A better grasp of how nerves influence the osteogenic immune microenvironment may lead to new strategies that integrate the nervous,immune,and skeletal systems to promote bone regeneration.
基金funded by a grant from the National Natural Science Foundation of China(82572785,82172489,82172449)funding for young investigators of PLA(2022-JCJQ-QT-004)。
文摘Estrogen deficiency after menopause accelerates bone loss by stimulating osteoclast formation and activity,but the molecular pathways that link estrogen signaling to osteoclast regulation remain incompletely defined.Here,we identify the sialyltransferase ST3GAL-I as a key mediator of RANKL-induced osteoclastogenesis.RANKL activates c-FOS to drive ST3GAL1 transcription,whereas estrogen-bound ERαcompetes with TRAF6 and suppresses this c-FOS–dependent induction.In a clinical cohort of pre-menopausal and post-menopausal women with or without osteoporosis,serum total andα-2,3-linked sialic acid levels increased with age and were highest in post-menopausal osteoporotic patients.Single-cell RNA sequencing of human bone revealed that osteoclasts form a prominent cluster only after menopause,where FOS,CTSK,and ST3GAL1 are strongly co-expressed,and the estrogen-responsive gene PGR is down-regulated.Additionally,in vivo experiments showed that sialidase treatment in estrogen-deficient models effectively reduced osteoclast-mediated bone loss,mimicking the effects of estradiol.These findings define a direct molecular link between loss of estrogen and activation of a FOS–ST3GAL1 sialylation pathway in osteoclasts,providing mechanistic insight into the enhanced bone resorption characteristic of post-menopausal osteoporosis.
基金The authors thank Justine C.Lee,MD,PhD of UCLA for providing the artwork for the figures.The reported work was supported in part by research grants from The American Society of Plastic Surgeons/Plastic Surgery Foundation’s(PSF)Pilot Research Grant Program,and the American Society of Craniofacial Surgeons/Komedyplast Foundation Award.MB and EMF were recipients of the Pritzker Research Fellowship funded through a NIH T-35 training grant(NIDDK).MB was a recipient of the Alpha Omega Alpha Carolyn L.Kuckein Research Fellowship.RRR was a recipient of the Clinical Investigator Award/Mentored Research Award DE020140-01(NIDCR)from the National Institutes of Health.
文摘The normal growth and development of the skull is a tightly regulated process that occurs along the osteogenic interfaces of the cranial sutures.Here,the borders of the calvarial bones and neighboring tissues above and below,function as a complex.Through coordinated remodeling efforts of bone deposition and resorption,the cranial sutures maintain a state of patency from infancy through early adulthood as the skull continues to grow and accommodate the developing brain’s demands for expansion.However,when this delicate balance is disturbed,a number of pathologic conditions ensue;and if left uncorrected,may result in visual and neurocognitive impairments.A prime example includes craniosynostosis,or premature fusion of one or more cranial and/or facial suture(s).At the present time,the only therapeutic measure for craniosynostosis is surgical correction by cranial vault reconstruction.However,elegant studies performed over the past decade have identified several genes critical for the maintenance of suture patency and induction of suture fusion.Such deeper understandings of the pathogenesis and molecular mechanisms that regulate suture biology may provide necessary insights toward the development of non-surgical therapeutic alternatives for patients with cranial suture defects.In this review,we discuss the intricate cellular and molecular interplay that exists within the suture among its three major components:dura mater,osteoblastic related molecular pathways and osteoclastic related molecular pathways.
文摘Background Dehydroepiandrosterone （DHEA） is widely known for its beneficial effect on postmenopausal osteoporosis, although the underlying mechanisms remain mainly unclear. In this study, we tried to determine the activation of mitogen-activated protein kinase signal pathways during DHEA treatment and the indirect role of osteoblasts （OBs） on osteoclasts under the DHEA treatment of postmenopausal osteoporosis. Methods Primary human OBs and osteoclast-like cells were cultured and, we pretreated OBs with or without U0126 （a highly selective inhibitor of both MEK1 and MEK2）. The OBs were treated with DHEA. We then tested the effects of DHEA on human osteoblastic viability, osteoprotegerin production and the expression of phosphor-ERK1/2 （extracellular signal-regulated kinase）. In the presence or absence of OBs, the function of osteoclastic resorption upon DHEA treatment was calculated. Results DHEA promoted the human osteoblastic proliferation and inhibited the osteoblastic apoptosis within the concentration range of 108-106 mol/L （P 〈0.05, P 〈0.01, respectively）. Within the effective concentration range, the expression of phosphor-ERK1/2 and osteoprotegerin was increased by DHEA and blocked by U0126. In the presence of OBs, DHEA could significantly decrease the number and the area of bone resorption lacuna （P 〈0.05 and P 〈0.01, respectively）. Without OBs, however, the effects of DHEA on the bone resorption lacuna were almost completely abolished. Conclusions DHEA could indirectly inhibit the human osteoclastic resorption through promoting the osteoblastic viability and osteoprotegerin production, which is mediated by mitogen-activated protein kinases signal pathway involving the phosphor-ERK1/2.
基金supported by the National Natural Science Foundation of China(NSFC)(No.82130073,No.82372430,No.31871431,No.31821002,No.32101011,No.22177073)Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal System+3 种基金Shanghai Science and Technology Committee(No.23ZR1437600,No.24410710600,No.24141901302)Shenzhen Medical Research Fund(No.B2302005)The Open Project Funding of Shanghai Key Laboratory of Orthopedics(No.KFKT202201)Biomaterials and Regenerative Medicine Institute Cooperative,Research Project,Shanghai Jiao Tong University School of Medicine(No.2022LHA01).
文摘Itaconate,a macrophage-specific anti-inflammatory metabolite,has recently emerged as a critical regulator in rheumatoid arthritis pathogenesis.We found that itaconate is a TNF-αresponsive metabolite significantly elevated in the serum and synovial fluid of rheumatoid arthritis patients and we demonstrated that itaconate is primarily produced by inflammatory macrophages rather than osteoclasts or osteoblasts.In TNF-transgenic and Irg1−/−hybrid mice,a more severe bone destruction phenotype was observed.
基金supported by grants from the National Natural Science Foundation of China(Nos.81572852 and 82104671)the Great Program of the Science Foundation of Tianjin(No.18JCZDJC33200)+1 种基金Heilongjiang Province Fund(No.LH2020H102)Tianjin Key Medical Discipline(Specialty)Construction Project(No.TJYXZDXK-032A)。
文摘This study investigated the regulatory potential of salidroside(SAL),a primary active compound in Rhodiola rosea L.,on osteoclast differentiation by modulating the hypoxia-inducible factor 1-alpha(HIF-1α)pathway in osteoblasts.Luciferase reporter assay and chromatin immunoprecipitation(Ch IP)assay were employed to validate whether the receptor activator of nuclear factor-κB ligand(RANKL)is the downstream target gene of HIF-1αin osteoblasts.The study also utilized lipopolysaccharide(LPS)-induced mouse osteolysis to examine the impact of SAL on osteolysis in vivo.Furthermore,conditioned medium(CM)from SAL-pretreated osteoblasts was used to investigate the paracrine effects on osteoclastogenesis through the HIF-1αpathway.Hypoxic condition-induced overexpression of HIF-1αupregulated RANKL levels by binding to the RANKL promoter and enhancing transcription in osteoblastic cells.In vivo,SAL significantly alleviated bone tissue hypoxia and decreased the expression of HIF-1αby downregulating the expression of RANKL,vascular endothelial growth factor(VEGF),interleukin 6(IL-6),and angiopoietin-like 4(ANGPTL4).In the paracrine experiment,conditioned media from SAL-pretreated osteoblasts inhibited differentiation through the HIF-1α/RANKL,VEGF,IL-6,and ANGPTL4 pathways.RANKL emerges as the downstream target gene regulated by HIF-1αin osteoblasts.SAL significantly alleviates bone tissue hypoxia and bone loss in LPS-induced osteolysis through the HIF-1α/RANKL,VEGF,IL-6,and ANGPTL4 pathways.SAL inhibits osteoclast differentiation by regulating osteoblast paracrine secretion.
基金supported by the Natural Science Foundation of Guangdong Province,China(No.2021A1515012168)the Administration of Traditional Chinese Medicine of Guangdong Province,China(Nos.20221146 and 20241091)+5 种基金the Basic and Applied Basic Research Fund Project in Guangdong Province,China(No.2020A1515110948)the Basic and Applied Basic Research in Jointly Funded Projects of City Schools(Institutes)Projects,China(Nos.202201020500 and 202201020295)the Project of Guangzhou Science and Technology Department,China(No.202102021040)the Guangzhou Science and Technology Plan Project,China(No.2023B03J0379)the Chinese Society of Traditional Chinese Medicine Youth Talent Lifting Project(No.2022-QNRC2-B11)the Hospital Young and Middle-aged Key Talent Cultivation Project of The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine(2023-10)。
文摘Osteoporosis is a prevalent skeletal condition characterized by reduced bone mass and strength,leading to increased fragility.Buqi-Tongluo(BQTL)decoction,a traditional Chinese medicine(TCM)prescription,has yet to be fully evaluated for its potential in treating bone diseases such as osteoporosis.To investigate the mechanism by which BQTL decoction inhibits osteoclast differentiation in vitro and validate these findings through in vivo experiments.We employed MTS assays to assess the potential proliferative or toxic effects of BQTL on bone marrow macrophages(BMMs)at various concentrations.TRAc P experiments were conducted to examine BQTL's impact on osteoclast differentiation.RT-PCR and Western blot analyses were utilized to evaluate the relative expression levels of osteoclast-specific genes and proteins under BQTL stimulation.Finally,in vivo experiments were performed using an osteoporosis model to further validate the in vitro findings.This study revealed that BQTL suppressed receptor activator of NF-κB ligand(RANKL)-induced osteoclastogenesis and osteoclast resorption activity in vitro in a dose-dependent manner without observable cytotoxicity.The inhibitory effects of BQTL on osteoclast formation and function were attributed to the downregulation of NFATc1 and c-fos activity,primarily through attenuation of the MAPK,NF-κB,and Calcineurin signaling pathways.BQTL's inhibitory capacity was further examined in vivo using an ovariectomized(OVX)rat model,demonstrating a strong protective effect against bone loss.BQTL may serve as an effective therapeutic TCM for the treatment of postmenopausal osteoporosis and the alleviation of bone loss induced by estrogen deficiency and related conditions.
基金supported by GILO Foundation.This research is in part supported by Korea Drug Development Fund funded by Ministry of Science and ICT,Ministry of Trade,Industry,and Energy,and Ministry of Health and Welfare(RS-2023-00282595,Republic of Korea).
文摘Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19 is important for its function in osteoclast differentiation,and LEL-Fc,a competitive inhibitor of Tm4sf19,effectively suppresses osteoclast multinucleation and prevent bone loss associated with osteoporosis.This study aimed to investigate the role of Tm4sf19 in RA,an inflammatory and abnormal osteoclast disease,using a mouse model of collagen-induced arthritis(CIA).Tm4sf19 expression was observed in macrophages and osteoclasts within the inflamed synovium,and Tm4sf19 expression was increased together with inflammatory genes in the joint bones of CIA-induced mice compared with the sham control group.Inhibition of Tm4sf19 by LEL-Fc demonstrated both preventive and therapeutic effects in a CIA mouse model,reducing the CIA score,swelling,inflammation,cartilage damage,and bone damage.Knockout of Tm4sf19 gene or inhibition of Tm4sf19 activity by LEL-Fc suppressed LPS/IFN-γ-induced TLR4-mediated inflammatory signaling in macrophages.LEL-Fc disrupted not only the interaction between Tm4sf19 and TLR4/MD2,but also the interaction between TLR4 and MD2.μCT analysis showed that LEL-Fc treatment significantly reduced joint bone destruction and bone loss caused by hyperactivated osteoclasts in CIA mice.Taken together,these findings suggest that LELFc may be a potential treatment for RA and RA-induced osteoporosis by simultaneously targeting joint inflammation and bone destruction caused by abnormal osteoclast activation.
基金Supported by 2024 Yeungnam University Research Grant.
文摘Ankylosing spondylitis(AS)is a chronic,progressive,systemic autoimmune disease characterised by spinal stiffness and ocular,cardiac,intestinal,and peripheral joint involvements.Genetics,infectious agents,and immune-mediated inflammatory processes have all been hypothesized to contribute to AS pathogenesis,but the precise aetiology remains elusive.Recent studies have identified biological and cellular factors that correlate with the onset and progression of AS.This has provided avenues of research that may help elucidate disease mechanisms and lead to advances in therapeutic interventions.This study aimed to examine some of the findings from recent molecular studies,focusing on the molecular mechanism and associated factors such as interleukin-17,tumor necrosis factor-alpha,receptor activator of nuclear factor-kappa B/receptor activator of nuclear factor-kappa B ligand/osteoprotegerin pathway,and related micro-RNAs to gain insight into aberrant bone formation in AS and potential approaches to its prevention.This editorial also addresses the contribution of osteoclasts to bone pathology in AS.The author examined the molecular pathways governing osteoclast differentiation and activity,with particular emphasis on relevant cytokines and immune cell interactions.A comprehensive understanding of these mechanisms is essential for the development of targeted therapies to mitigate excessive bone resorption and pathological skeletal remodeling in AS.
基金the funding support from the Tianjin Medical University“Clinical Talent Training 123 Climbing Plan”the Youth Fund of Tianjin Medical University Second Hospital(No.2022ydey06)。
文摘Polyetheretherketone(PEEK)is a desirable candidate to replace conventional metal implants owing to its excellent mechanical properties.However,the intrinsic bioinertness of PEEK results in inferior or delayed osseointegration,which limits its further clinical application.To address these challenges,one leading strategy is to construct a biofunctionalized surface on PEEK that provides a coordinated osteoblastosteoclast interactions microenvironment.Herein,alendronate(ALN),a common bone absorption inhibitor,was loaded in biomedical inorganic/organic microspheres,consisting of bioactive inorganic nanohydroxyapatite core,and chitosan(CS)shell.Polydopamine(PDA)modification was employed to ensure the adherence of the microspheres to the PEEK surface.The delivery of ALN and Ca^(2+)from these microspheres simultaneously suppressed osteoclastogenesis and promoted osteogenesis,resulting in a coordinated cascade of osteoblast-osteoclast interactions crucial for the per-implant osseointegration.In vitro experiments demonstrated that the PEEK surface exhibited satisfactory biocompatibility and enhanced the proliferation and osteogenic differentiation of rat bone mesenchymal stem cells while inhibiting the osteoclast differentiation.Moreover,the in vivo rat femoral drilling model demonstrated superior osseointegration three months after implantation.By considering the bone remodeling processes,this study proposes a novel biofunctionalized PEEK surface that regulates the activities of both osteoblasts and osteoclasts to promote osseointegration.
基金supported by National Natural Science Foundation of China(82204766,82074122,82174078)Natural Science Foundation of Hunan province(2023JJ40490)+9 种基金Changjiang Scholars Program in Ministry Education,People’s Republic of China(T2019133)Xiaohe Sci-Tech Talents Special Funding under Hunan Provincial Sci-Tech Talents Sponsorship Program(2023TJ-X71)Science and Technology Innovation Program of Hunan Province(2024RC3201)Scientific research project of Hunan Provincial Education Department(21B0394,21A0239)Research Project of Hunan Administration of Traditional Chinese Medicine(B2023055)Changsha Outstanding Innovative Youth Training Program(kq2306021)Outstanding Youth Program of Hunan University of Chinese Medicine(202202)Postgraduate Innovation Project of Hunan University of Chinese Medicine(2024CX090)Open Foundation Project of Hunan International Joint Laboratory of Traditional Chinese Medicine(2022GJSYS02)Undergraduate Research and Innovation Foundation of Hunan University of Chinese Medicine(2023BKS097).
文摘Abnormal activation of macrophages and osteoclasts(OCs)contributes significantly to rheumatoid arthritis(RA)development by secretion of numerous inflammatory factors.Notably,these cells exhibit significant upregulation of folate receptor proteins on their surfaces.Unfortunately,there is a current lack of safe and effective therapeutic drugs for RA.Xuetongsu(XTS),a triterpenoid compound extracted fromKadsura heteroclita Roxb Craib,has demonstrated the ability to significantly inhibit the proliferation of RA fibroblast-like synoviocytes(RAFLS).However,its clinical application is hampered by poor targeting and short half-life.To address these drawbacks,we previously developed a nano-drug system named HRPS nanoparticles(NPs),which effectively targets RAFLS and inhibits synovial hyperplasia.However,this system overlooked the essential role of OCs in RA-related bone destruction.Therefore,we designed a novel folate-modified biomimetic Prussian blue(PB)-XTS NP(FMPX NP)for the selective delivery of XTS into inflammatory macrophages and OCs.The NP exhibits an excellent photothermal effect when assisted by laser irradiation,facilitating targeted release of XTS within inflammatory macrophages and OCs.The synergistic anti-inflammatory and reactive oxygen species scavenging effects of PB NPs and XTS are mediated by the inhibition of the NF-κB signaling pathway in inflammatory macrophages and RANK/RANKL/NFATc1 signaling pathway in OCs.In vivo experiments showed that FMPX NPs extended the half-life of XTS by 2.32 times,decreased hind foot swelling from 12.10±0.49 mm to 8.24±0.09 mm in the model group,and prevented bone damage.In conclusion,this study introduces a novel dual-targeted nano-based therapy for RA joints and highlights its potential for biochemical photothermal triple therapy for RA.FMPX NPs inhibit arthritis-related inflammation and bone destruction through a dual-target strategy,providing new insights for targeted drug therapies in clinical RA treatment.
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 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 National Natural Science Foundation of China(U22A20374).
文摘Rheumatoid arthritis(RA)is a progressive autoimmune disease characterized by bone destruction that is primarily caused by the overactivation of osteoclasts(OCs),which are critical therapeutic targets.Triptolide(TP)has strong anti-RA effects but is limited by its narrow therapeutic window and associated toxicity,necessitating combination therapy to increase its efficacy and reduce side effects.Medicarpin(Med),a flavonoid with anti-inflammatory and anti-bone destruction properties,has shown potential in reducing osteoclastogenesis.However,the mechanisms underlying the synergistic effects of TP and Med on RA treatment remain unclear.We addressed this issue by evaluating the effects of TP,Med,and their combination on a collagen-induced arthritis(CIA)rat model,with a focus on bone erosion as the primary research endpoint.We subsequently performed experimental validation in an in vitro OC dif-ferentiation model to assess the impacts of these treatments on OC formation and function.Based on polymerase chain reaction(PCR)microarray data from RA patients,further investigations focused on N^(6)-methyladenosine(m^(6)A)methylation and its regulatory factors,methyltransferase-like 3(METTL3)and YT521-B homology domain family protein 1(YTHDF1),which have been identified as potential tar-gets of TP and Med.Key findings revealed that the TP and Med combination significantly alleviated bone destruction and inhibited OC differentiation,exerting stronger effects at lower doses than either drug alone.Mechanistically,TP and Med synergistically modulated METTL3 and YTHDF1 to suppress osteo-clastogenesis through distinct m6 A methylation pathways,contributing to the mitigation of RA-associated bone destruction.Overall,our data highlight the potential of the m^(6)A modification as a ther-apeutic mechanism for the combined use of TP and Med for RA treatment,providing a theoretical basis for the clinical application of herbal active ingredient combinations.
