Bone is a highly calcified and vascularized tissue.The vascular system plays a vital role in supporting bone growth and repair,such as the provision of nutrients,growth factors,and metabolic waste transfer.Moreover,th...Bone is a highly calcified and vascularized tissue.The vascular system plays a vital role in supporting bone growth and repair,such as the provision of nutrients,growth factors,and metabolic waste transfer.Moreover,the additional functions of the bone vasculature,such as the secretion of various factors and the regulation of bone-related signaling pathways,are essential for maintaining bone health.In the bone microenvironment,bone tissue cells play a critical role in regulating angiogenesis,including osteoblasts,bone marrow mesenchymal stem cells(BMSCs),and osteoclasts.Osteogenesis and bone angiogenesis are closely linked.The decrease in osteogenesis and bone angiogenesis caused by aging leads to osteoporosis.Long noncoding RNAs(lncRNAs)are involved in various physiological processes,including osteogenesis and angiogenesis.Recent studies have shown that lncRNAs could mediate the crosstalk between angiogenesis and osteogenesis.However,the mechanism by which lncRNAs regulate angiogenesis-osteogenesis crosstalk remains unclear.In this review,we describe in detail the ways in which lncRNAs regulate the crosstalk between osteogenesis and angiogenesis to promote bone health,aiming to provide new directions for the study of the mechanism by which lncRNAs regulate bone metabolism.展开更多
Titanium(Ti)and its alloys have been extensively explored for treating load-bearing bone defects.How-ever,high-stress shielding,weak osteogenic activity,and insufficient vascularization remain key chal-lenges for the ...Titanium(Ti)and its alloys have been extensively explored for treating load-bearing bone defects.How-ever,high-stress shielding,weak osteogenic activity,and insufficient vascularization remain key chal-lenges for the long-term clinical outcomes of Ti-based implants.Herein,inspired by structural and func-tional cues of bone regeneration,a silicon-doped nano-hydroxyapatite(nSiHA)/titanium dioxide(TiO_(2))composite coating with a hierarchical micro/nano-network structure is constructed on the surface of a 3D-printed porous Ti scaffold via a combined strategy of acid-alkali(AA)treatment and electrochemi-cal deposition technique,which not only endows the scaffold with excellent osteoinduction ability but can also effectively immobilize and release vascular endothelial growth factor(VEGF).The results of the in vitro cell experiments show that the functionalized Ti scaffold significantly promotes osteogenesis in bone marrow mesenchymal stem cells(BMSCs)and angiogenesis in human umbilical vein endothelial cells(HUVECs)by activating the extracellular signal-regulated protein kinase(ERK)and HIF-1αsignaling pathways.After being implanted into a rat femoral condyle defect model,the functionalized Ti scaffold can induce in situ vascularized bone regeneration by orchestrating the two coupled processes of angio-genesis and osteogenesis.These findings indicate that the functionalized Ti scaffold has great potential in bone tissue regeneration and is a promising candidate for load-bearing bone defect repair.展开更多
Radium-223(^(223)Ra)is a bone-seeking,alpha-particle-emitting radionuclide that is approved for the treatment of patients with metastatic prostate cancer and is currently being tested in clinical trials for primary an...Radium-223(^(223)Ra)is a bone-seeking,alpha-particle-emitting radionuclide that is approved for the treatment of patients with metastatic prostate cancer and is currently being tested in clinical trials for primary and metastatic cancers to the bone.^(223)Ra accumulates in mineralized bone areas with high bone turnover,where its effects are confined within 100μm of the bone-marrow interface due to the short tissue penetrance of the alpha particles.A recent clinical study has shown a significantly increased fracture rate associated with the administration of^(223)Ra,mostly in tumor-free bones.Importantly,the biological mechanisms underlying this bone fragility remain unclear.In this work,we combined micro-computed tomography and mechanical studies with ex vivo spatial biology analysis based on 3D fluorescence microscopy to clarify the effects of^(223)Ra on bone and key bone stromal cell components.We found that^(223)Ra caused major trabecular bone loss with no detectable impact on cortical bone.In addition,^(223)Ra impaired osteoblast bone-forming activity,which was paralleled by a transient increase in osteoclast number and long-term adipocyte formation.Overall,these results suggest that the impact of^(223)Ra on bone health is orchestrated by multiple bone stromal cell components.^(223)Ra-mediated trabecular bone loss was prevented by administration of zoledronic acid,which should always be combined with^(223)Ra.展开更多
The bone repair niche,including the physiological and pathological microenvironment,is a complex system that interferes with various cellular/noncellular activities.Thus,a rational perspective of designing tunable bio...The bone repair niche,including the physiological and pathological microenvironment,is a complex system that interferes with various cellular/noncellular activities.Thus,a rational perspective of designing tunable biomaterials with the modulation of the bone microenvironment is in high demand in pre/clinical practice for the management of refractory bone defects in combination with severe bone diseases.Two-dimensional(2D)layered materials are emerging biomaterials for bone microenvironment engineering because of their inherent biocompatibility,osteo-inductivity,osteo-conductivity,optical properties,enzyme mimetics,and mechanical properties.In this study,we focus on the latest advances in developing 2D layered materials in bone regeneration,bone cancer therapies,bone-related infections eradication,and articular cartilage repair.In addition,the specific action mechanisms and design regimens of 2D-layered material-based nanoplatforms are clarified.Finally,the current challenges are discussed,and the key inspirations for further broadening the pre/clinical applications of 2D layered materials in orthopedic disorder therapy are proposed.展开更多
Bone metastasis is the leading cause of death in prostate cancer patients,for which there is currently no effective treatment.Since the bone microenvironment plays an important role in this process,attentions have bee...Bone metastasis is the leading cause of death in prostate cancer patients,for which there is currently no effective treatment.Since the bone microenvironment plays an important role in this process,attentions have been directed to the interactions between cancer cells and the bone microenvironment,including osteoclasts,osteoblasts,and bone stromal cells.Here,we explained the mechanism of interactions between prostate cancer cells and metastasis-associated cells within the bone microenvironment and further discussed the recent advances in targeted therapy of prostate cancer bone metastasis.This review also summarized the effects of bone microenvironment on prostate cancer metastasis and the related mechanisms,and provides insights for future prostate cancer metastasis studies.展开更多
Recent evidence highlights multifaceted biological needs to recapitulate the bone microenvironment for bone regeneration.Neurotization has great potential for realizing multi-system modulations in bone tissue engineer...Recent evidence highlights multifaceted biological needs to recapitulate the bone microenvironment for bone regeneration.Neurotization has great potential for realizing multi-system modulations in bone tissue engineering(BTE).However,a neural strategy involving all the key bone repair steps temporally has not yet been reported.In this study,we reported the neural tissue engineering hydrogel-encapsulated Schwann cell-derived exosomes(SC Exo).This sustained-release SC Exo system prominently enhanced bone regeneration by promoting innervation,immunoregulation,vascularization,and osteogenesis in vivo.Moreover,the in vitro results further confirmed that this system significantly induced M2 polarization of macrophages,tube formation of HUVECs,and BMSCs osteogenic differentiation.Furthermore,BMSCs osteogenesis was promoted by upregulating the TGF-β1/SMAD2/3 signaling pathway.In summary,a novel cell-free and easily prepared SC Exo neural engineering was successfully developed to promote bone regeneration by orchestrating the entire bone healing microenvironment,which may provide a new strategy for tissue engineering and clinical treatment of bone defects.展开更多
Osteoarthritis(OA)is a progressive degenerative joint sickness related with mechanics,obesity,ageing,etc.,mainly characterized by cartilage degeneration,subchondral bone damage and synovium inflammation.Coordinated me...Osteoarthritis(OA)is a progressive degenerative joint sickness related with mechanics,obesity,ageing,etc.,mainly characterized by cartilage degeneration,subchondral bone damage and synovium inflammation.Coordinated mechanical absorption and conduction of the joint play significant roles in the prevalence and development of OA.Subchondral bone is generally considered a load-burdening tissue where mechanosensitive cells are resident,including osteocytes,osteoblast lineage cells,and osteoclast lineage cells(especially less concerned in mechanical studies).Mechano-signaling imbalances affect complicated cellular events and disorders of subchondral bone homeostasis.This paper will focus on the significance of mechanical force as the pathogenesis,involvement of various mechanical force patterns in mechanosensitive cells,and mechanobiology research of loading devices in vitro and in vivo,which are further discussed.Additionally,various mechanosensing structures(e.g.,transient receptor potential channels,gap junctions,primary cilia,podosome-associated complexes,extracellular vesicles)and mechanotransduction signaling pathways(e.g.,Ca^(2+) signaling,Wnt/β-catenin,RhoA GTPase,focal adhesion kinase,cotranscriptional activators YAP/TAZ)in mechanosensitive bone cells.Finally,we highlight potential targets for improving mechanoprotection in the treatment of OA.These advances furnish an integration of mechanical regulation of subchondral bone homeostasis,as well as OA therapeutic approaches by modulating mechanical homeostasis.展开更多
Objective： The aim of the study was to investigate the expression pattern of hematopoietic transcription factor GATA-1, -2 and -3 genes in leukemic bone marrow （BM） micreenvironment [including bone marrow stremal c...Objective： The aim of the study was to investigate the expression pattern of hematopoietic transcription factor GATA-1, -2 and -3 genes in leukemic bone marrow （BM） micreenvironment [including bone marrow stremal cells （BMSCs） and BM hematopoietic cells]. Methods： Mononuclear cells were isolated from BM of patients with acute myeloid leukemia （AML）, chronic myelogenous leukemia （CML）, or acute lymphoblasUc leukemia （ALL）. Adherent cells （BMSCs） and nonadherent ceils （BM hematopoietic cells） were collected after long-term culture in vitro. The semi-quantitative expression levels of GATA genes in the BMSCs or BM hematopoietic cells from patients with leukemia were analyzed by using RT-PCR-ELISA and com- pared with normal controls. Results： The expression level of GATA-1 gene in the BMSCs from CML group was significantly lower than that of the normal controls. The expression level of GATA-3 gene in the BMSCs from ALL was higher than that of the normal controls, but that from CML was lower than the normal controls. Dominant expression of GATA-3 gene was found in the normal BM hematopoietic cells. The dominant expression of GATA-2 gene was found in the normal BMSCs and the BMSCs from CML, whereas the dominant expression of GATA-3 gene was detected in the BMSCs from AML. Conclusion： GATA-1, -2 and -3 genes might play a role in hematopoiesis regulation in leukemia, and the changes of expression pattern of GATA genes might influence the hematopoiesis in BM microenvironment and relate to the pathogenesis and development of leukemia.展开更多
With lanthanum(La) in agriculture, medicine, and the chemical industry, La shows accumulation in the body, especially in the bone, because of its similar structure to calcium. Moreover, La has a direct role in bone fo...With lanthanum(La) in agriculture, medicine, and the chemical industry, La shows accumulation in the body, especially in the bone, because of its similar structure to calcium. Moreover, La has a direct role in bone formation regulating osteoblasts and osteoclasts. Nevertheless, bone formation is complex under the regulation of osteogenesis, osteoclastogenesis, and angiogenesis in the bone microenvironment. It is difficult to comprehensively understand the regulation of bone homeostasis from a single kind of cell.Herein, some bone microenvironment-related cells and mouse calvaria culture models were used to study the regulatory effect of La-based compound-lanthanum nitrate(La(NO_(3))_(3)) on bone formation.La(NO_(3))_(3) has good biological safety, and the osteogenic differentiation is significantly increased under La(NO_(3))_(3) treatment for bone marrow mesenchymal stem cells(BMMSC). In contrast, the differentiation,maturation, and bone erosion ability of osteoclasts are significantly decreased. Meanwhile, the angiogenesis ability of human umbilical vein endothelial cells(HUVEC) is significantly promoted when treated with La(NO_(3))_(3). Furthermore, bone metabolism and angiogenesis are improved under La(NO_(3))_(3) treatment in the calvaria ex vivo culture model and BMMSC-HUVEC co-culture system. These results suggest that La has the beneficial effect of promoting bone metabolism and improving bone formation in the bone microenvironment.展开更多
To study the expression of the bFGF and its receptor in the mouse bone marrow by treatment with acute radioactive injury and Ligustrazine, 56 mice were divided into 3 groups: normal group, radiation injured group and...To study the expression of the bFGF and its receptor in the mouse bone marrow by treatment with acute radioactive injury and Ligustrazine, 56 mice were divided into 3 groups: normal group, radiation injured group and Ligustrazine group. After irradiation by 6.0 Gy 60 Co γ ray, each mouse was orally given 0.1 ml Ligustrazine twice a day for 13 days in Ligustrazine group, and each mouse in radiation injured group was orally given equal amount of saline. On the 3rd, 7th, 14th day after irradiation, bone marrow mono nuclear cells (BMMNC) were counted, and the expression levels of bFGF and bFGFR in bone marrow were evaluated by immunohistochemistry and flow cytometry analysis respectively. On the 3rd, 7th, 14th day after irradiation, expression of bFGF in bone marrow were significantly lower than in normal group ( P <0.05 or P <0.01). Expressions of bFGF and bFGFR were much higher in Ligustrazine treated group than that in the control group ( P <0.05 or P <0.01). Ligustrazine potentiate the expression of bFGF and bFGFR in bone marrow MNC to recover the bone marrow hematopoiesis inductive microenvironment, which is one of the mechanisms by which Ligustrazine rebuild the bone marrow hematopoiesis after acute radioactive injury.展开更多
Multiple myeloma(MM)is a hematological malignancy characterized by the accumulation of immunoglobulin-secreting clonal plasma cells at the bone marrow(BM).The interaction between MM cells and the BM microenvironment,a...Multiple myeloma(MM)is a hematological malignancy characterized by the accumulation of immunoglobulin-secreting clonal plasma cells at the bone marrow(BM).The interaction between MM cells and the BM microenvironment,and specifically BM mesenchymal stem cells(BM-MSCs),has a key role in the pathophysiology of this disease.Multiple data support the idea that BM-MSCs not only enhance the proliferation and survival of MM cells but are also involved in the resistance of MM cells to certain drugs,aiding the progression of this hematological tumor.The relation of MM cells with the resident BM-MSCs is a two-way interaction.MM modulate the behavior of BM-MSCs altering their expression profile,proliferation rate,osteogenic potential,and expression of senescence markers.In turn,modified BM-MSCs can produce a set of cytokines that would modulate the BM microenvironment to favor disease progression.The interaction between MM cells and BM-MSCs can be mediated by the secretion of a variety of soluble factors and extracellular vesicles carrying microRNAs,long non-coding RNAs or other molecules.However,the communication between these two types of cells could also involve a direct physical interaction through adhesion molecules or tunneling nanotubes.Thus,understanding the way this communication works and developing strategies to interfere in the process,would preclude the expansion of the MM cells and might offer alternative treatments for this incurable disease.展开更多
Objective: To explore the effect of gamma irradiation on nuclear factor-kappa B in cultured bone marrow stromal cells. Methods: Immunocytochemistry, Western blot and electrophoretic mobility shift assay (EMSA) were us...Objective: To explore the effect of gamma irradiation on nuclear factor-kappa B in cultured bone marrow stromal cells. Methods: Immunocytochemistry, Western blot and electrophoretic mobility shift assay (EMSA) were used. Results: The expression of NF-kB in cultured mouse bone marrow stromal cells (BM-SCs) on the level of protein was elevated after exposure to 60Co in the dosage of 8. 0 Gy with the use of im-munocytochemistry and Western blot. The activity of nuclear factor-kappa B in cultured BMSCs was significantly increased after exposure to gamma irradiation by using EMSA. The activity peak was at the 4th h after irradiation. Conclusion: Our results suggest that the activation of nuclear factor-kappa B in the BMSCs after irradiation may be involved in the protection of BMSCs against apoptosis and in the recovery of hematopoiesis after radiation.展开更多
Diabetic conditions impair bone regeneration due to dysregulated macrophage polarization and inflammatory imbalance.Current therapies often fail to address systemic immune homeostasis.Herein,a bone-targeted nanoplatfo...Diabetic conditions impair bone regeneration due to dysregulated macrophage polarization and inflammatory imbalance.Current therapies often fail to address systemic immune homeostasis.Herein,a bone-targeted nanoplatform(abbreviated as AgSr-MSNs)is engineered to scavenge excess nitric oxide(NO)and respond to the acidic diabetic microenvironment based on upregulated inducible nitric oxide synthase(iNOS)expression in M1 macrophages residing within both the diabetic bone marrow and localized osteolytic regions in our study.The system integrates silver sulfide quantum dots(Ag2S QDs)and Sr^(2+)into mesoporous silica nanoparticles(MSNs),encapsulated with rhodamine/β-cyclodextrin and surface-modified with alendronate for bone-specific targeting.Under near-infrared(NIR)irradiation,the nanoparticles induce macrophage repolarization toward M2 phenotypes through JAK/STAT signaling pathway,followed by upregulating anti-inflammatory mediators(TGF-β,PD-L1)and tissue-regenerative factors(BMP-2/4,VEGF-B),while suppressing pro-inflammatory cytokines(CCR2,S100A4).This dual NO/pH-responsive platform synergistically mitigates inflammatory dysregu-lation,enhances osteogenesis,and promotes angiogenesis.In diabetic models,systemic administration with NIRmediated mild hyperthermia reduces CD86^(+)macrophages and TNF-αlevels while elevating CD206^(+)macrophages locally and systemically.Concurrently,it boosts CD31,Runx2,and osteocalcin(OCN)expression levels at defect sites,indicating restored vascularization and osteogenesis.This strategy addresses the pathological triad of diabetic osteopathy-chronic inflammation,vascular insufficiency,and osteogenic impairment-providing a translatable nanotherapeutic paradigm for metabolic bone disorders.展开更多
The role of bone marrow(BM)compensatory response in autoimmune hemolytic anemias(AIHAs)is emerging and inadequate reticulocytosis has been associated with more severe disease and adverse outcomes.However,few is known ...The role of bone marrow(BM)compensatory response in autoimmune hemolytic anemias(AIHAs)is emerging and inadequate reticulocytosis has been associated with more severe disease and adverse outcomes.However,few is known about the BM immunologic microenvironment composition in these diseases.Here we investigated BM features in a large cohort of 97 patients with autoimmune hemolytic anemia(AIHA)and observed a high prevalence of hypercellularity,dyserythropoiesis,reticulin fibrosis,and T-cell infiltration(65%,29%,76%,and 69%of patients,respectively).These findings were associated with inadequate bone marrow compensation,more severe anemia at onset,and need of multiple treatments.In a subset of warm type AIHA patients we investigated BM microenvironment by single-cell RNA sequencing.We found distinct immune cell profiles across disease stages(diagnosis,remission,relapse).In particular,upregulation of inflammatory response pathways was noted in CD8+,CD4+,and monocyte subsets during relapse compared to diagnosis and remission.Moreover,by single-cell TCR sequencing,we found small T cell clones at diagnosis that may either disappeared or expanded at remission.Disappearing clones exhibited a naive CD8+phenotype and were more likely to respond to glucocorticoid treatment.Expanding clones showed upregulation of cytotoxic T cell markers and may play a role in the transition to a chronic/relapsing phase.Finally,cytokine gene expression differed across disease phases.At relapse,pro-inflammatory cytokines such as TNF-alpha,IL-1,and IL-6 were upregulated in CD4+and CD8+T cells,while TGF-beta was downregulated,potentially in an attempt to counteract the transition to chronic phase.This is the largest study evaluating BM histology and clinical characteristics,and the first evaluation of BM microenvironment by single-cell RNA sequencing in AIHA.We showed a complex scenario encompassing T-cell infiltration,clonality,and up/down-regulation of cytokine genes,associated with a more severe and relapsing disease.展开更多
Epithelial-mesenchymal transition （EMT） in cancer describes the phenotypic and behavioral changes of cancer cells from indolent to virulent forms with increased migratory, invasive and metastatic potential. EMT can ...Epithelial-mesenchymal transition （EMT） in cancer describes the phenotypic and behavioral changes of cancer cells from indolent to virulent forms with increased migratory, invasive and metastatic potential. EMT can be induced by soluble proteins like transforming growth factor β1 （TGFβ1） and transcription factors including Snail and Slug. We utilized theARCaPE/ARCaPM prostate cancer progression model and LNCaP clones stably overexpressing Snail to identify novel markers associated with EMT. Compared to ARCaPE cells, the highly tumorigenic mesenchymal ARCaPM and ARCaPM1 variant cells displayed a higher incidence of bone metastasis after intracardiac administration in SCID mice. ARCaPM and ARCaPM1 expressed mesenchymal stromal markers of vimentin and N-cadherin in addition to elevated levels of Receptor Activator of NF-κB Ligand （RANKL）. We observed that both epidermal growth factor （EGF） plus TGFβ1 treatment and Snail overexpression induced EMT in ARCaPE and LNCaP cells, and EMT was associated with increased expression of RANKL protein. Finally, we determined that the RANKL protein was functionally active, promoting osteoclastogenesis in vitro. Our results indicate that RANKL is a novel marker for EMT during prostate cancer progression. RANKL may function as a link between EMT, bone turnover, and prostate cancer skeletal metastasis.展开更多
Critical-sized bone defects represent a significant clinical challenge due to their inability to undergo spontaneous regeneration,necessitating graft interventions for effective treatment.The development of tissue-eng...Critical-sized bone defects represent a significant clinical challenge due to their inability to undergo spontaneous regeneration,necessitating graft interventions for effective treatment.The development of tissue-engineered scaffolds and regenerative medicine has made bone tissue engineering a highly viable treatment for bone defects.The physical and biological properties of nanocomposite biomaterials,which have optimized structures and the ability to simulate the regenerative microenvironment of bone,are promising for application in the field of tissue engineering.These biomaterials offer distinct advantages over traditional materials by facilitating cellular adhesion and proliferation,maintaining excellent osteoconductivity and biocompatibility,enabling precise control of degradation rates,and enhancing mechanical properties.Importantly,they can simulate the natural structure of bone tissue,including the specific microenvironment,which is crucial for promoting the repair and regeneration of bone defects.This manuscript provides a comprehensive review of the recent research developments and applications of structure-optimized and microenvironment-inspired nanocomposite biomaterials in bone tissue engineering.This review focuses on the properties and advantages these materials offer for bone repair and tissue regeneration,summarizing the latest progress in the application of nanocomposite biomaterials for bone tissue engineering and highlighting the challenges and future perspectives in the field.Through this analysis,the paper aims to underscore the promising potential of nanocomposite biomaterials in bone tissue engineering,contributing to the informed design and strategic planning of next-generation biomaterials for regenerative medicine.展开更多
Given the limitations of allogeneic and artificial bone grafts,bone organoids have attracted extensive attention for their physiological properties that closely resemble natural bone,offering great potential to bone r...Given the limitations of allogeneic and artificial bone grafts,bone organoids have attracted extensive attention for their physiological properties that closely resemble natural bone,offering great potential to bone recon-struction for critical-sized bone defects.Although early-stage bone organoids such as osteo-callus organoids and woven bone organoids have been reported,functional bone organoids with vascularization and mineralization are currently unavailable due to the lack of bone-mimicking matrix and dynamic culture systems suitable for the long-term cultivation of mature bone organoids.Herein,a novel engineered bionic matrix hydrogels with multifunctional components and double network structure are developed by incorporating calcium phosphate oligomers(CPO)into a combination of bone-derived decellularized extracellular matrix(ECM)and salmon-derived deoxyribonucleic acid(DNA)via photo-crosslinking and dynamic self-assembly strategies.This kind of bionic matrix hydrogels facilitate recruitment,proliferation,osteogenesis and angiogenesis of bone marrow mesenchymal stromal cells(BMSCs).More importantly,vascularized and mineralized bone organoids are sequentially constructed using BMSCs-loaded engineered bionic matrix hydrogels via in vitro dynamic culture and in vivo heterotopic ossification.Meanwhile,this kind of engineered bionic matrix are capable of achieving efficient bone repair for cranial defect.These findings suggest that engineered bionic matrix hydrogels combined with such dynamic culture system,providing a promising strategy for functional bone organoids construction.展开更多
Using bone tissue engineering strategies to achieve bone defect repair is a promising modality.However,the repair process outcomes are often unsatisfactory.Here we properly designed a multi-functional microsphere syst...Using bone tissue engineering strategies to achieve bone defect repair is a promising modality.However,the repair process outcomes are often unsatisfactory.Here we properly designed a multi-functional microsphere system,which could deliver bioactive proteins under the dual response of ultrasound and microenvironment,release microenvironment-responsive products on demand,reverse bone injury microenvironment,regulate the immune microenvironment,and achieve excellent bone defect treatment outcomes.In particular,the MnO_(2) introduced into the poly(lactic-co-glycolic acid)(PLGA)microspheres during synthesis could consume the acid produced by the degradation of PLGA to protect bone morphogenetic protein-2(BMP-2).More importantly,MnO_(2) could consume reactive oxygen species(ROS)and produce Mn^(2+)and oxygen(O_(2)),further promoting the repair of bone defects while reversing the microenvironment.Moreover,the reversal of the bone injury microenvironment and the depletion of ROS promoted the polarization of M1 macrophages to M2 macrophages,and the immune microenvironment was regulated.Notably,the ultrasound(US)irradiation used during treatment also allowed the on-demand release of microenvironment-responsive products.The multi-functional microsphere system combines the effects of on-demand delivery,reversal of bone injury microenvironment,and regulation of the immune microenvironment,providing new horizons for the clinical application of protein delivery and bone defect repair.展开更多
Regardless of the advancement of synthetic bone substitutes,allograft-derived bone substitutes still dominate in the orthopaedic circle in the treatments of bone diseases.Nevertheless,the stringent devitalization proc...Regardless of the advancement of synthetic bone substitutes,allograft-derived bone substitutes still dominate in the orthopaedic circle in the treatments of bone diseases.Nevertheless,the stringent devitalization process jeopardizes their osseointegration with host bone and therefore prone to long-term failure.Hence,improving osseointegration and transplantation efficiency remains important.The alteration of bone tissue microenvironment(TME)to facilitate osseointegration has been generally recognized.However,the concept of exerting metal ionic cue in bone TME without compromising the mechanical properties of bone allograft is challenging.To address this concern,an interfacial tissue microenvironment with magnesium cationc cue was tailored onto the gamma-irradiated allograft bone using a customized magnesium-plasma surface treatment.The formation of the Mg cationic cue enriched interfacial tissue microenvironment on allograft bone was verified by the scanning ion-selective electrode technique.The cellular activities of human TERT-immortalized mesenchymal stem cells on the Mg-enriched grafts were notably upregulated.In the animal test,superior osseointegration between Mg-enriched graft and host bone was found,whereas poor integration was observed in the gamma-irradiated controls at 28 days post-operation.Furthermore,the bony in-growth appeared on magnesium-enriched allograft bone was significant higher.The mechanism possibly correlates to the up-regulation of integrin receptors in mesenchymal stem cells under modified bone TME that directly orchestrate the initial cell attachment and osteogenic differentiation of mesenchymal stem cells.Lastly,our findings demonstrate the significance of magnesium cation modified bone allograft that can potentially translate to various orthopaedic procedures requiring bone augmentation.展开更多
Bone marrow(BM)microenvironment regulates and supports the production of blood cells which are necessary to maintain homeostasis.In analogy to normal hematopoiesis,leukemogenesis is originated from leukemic stem cells...Bone marrow(BM)microenvironment regulates and supports the production of blood cells which are necessary to maintain homeostasis.In analogy to normal hematopoiesis,leukemogenesis is originated from leukemic stem cells(LSCs)which gives rise to more differentiated malignant cells.Leukemia cells occupy BM niches and reconstruct them to support leukemogenesis.The abnormal BM niches are the main sanctuary of LSCs where they can evade chemotherapy-induced death and acquire drug resistance.In this review,we focus on the protective effects of BM niche cells on acute lymphoblastic leukemia cells.展开更多
基金supported by the National Natural Science Foundation of China(No.81901430)the Guangdong Basic and Applied Basic Research Foundation(No.2022A1515010379)+1 种基金the Science and Technology Projects in Guangzhou(No.2023A04J0555)the Guangdong Provincial Key Laboratory of Physical Activity and Health Promotion(No.2021B1212040014),China.
文摘Bone is a highly calcified and vascularized tissue.The vascular system plays a vital role in supporting bone growth and repair,such as the provision of nutrients,growth factors,and metabolic waste transfer.Moreover,the additional functions of the bone vasculature,such as the secretion of various factors and the regulation of bone-related signaling pathways,are essential for maintaining bone health.In the bone microenvironment,bone tissue cells play a critical role in regulating angiogenesis,including osteoblasts,bone marrow mesenchymal stem cells(BMSCs),and osteoclasts.Osteogenesis and bone angiogenesis are closely linked.The decrease in osteogenesis and bone angiogenesis caused by aging leads to osteoporosis.Long noncoding RNAs(lncRNAs)are involved in various physiological processes,including osteogenesis and angiogenesis.Recent studies have shown that lncRNAs could mediate the crosstalk between angiogenesis and osteogenesis.However,the mechanism by which lncRNAs regulate angiogenesis-osteogenesis crosstalk remains unclear.In this review,we describe in detail the ways in which lncRNAs regulate the crosstalk between osteogenesis and angiogenesis to promote bone health,aiming to provide new directions for the study of the mechanism by which lncRNAs regulate bone metabolism.
基金supported by the Sichuan Science and Technology Program (Nos.2019JDTD0008 and 2022YFG0109)the China Postdoctoral Science Foundation (Nos.2021M692316 and 2020TQ0218).
文摘Titanium(Ti)and its alloys have been extensively explored for treating load-bearing bone defects.How-ever,high-stress shielding,weak osteogenic activity,and insufficient vascularization remain key chal-lenges for the long-term clinical outcomes of Ti-based implants.Herein,inspired by structural and func-tional cues of bone regeneration,a silicon-doped nano-hydroxyapatite(nSiHA)/titanium dioxide(TiO_(2))composite coating with a hierarchical micro/nano-network structure is constructed on the surface of a 3D-printed porous Ti scaffold via a combined strategy of acid-alkali(AA)treatment and electrochemi-cal deposition technique,which not only endows the scaffold with excellent osteoinduction ability but can also effectively immobilize and release vascular endothelial growth factor(VEGF).The results of the in vitro cell experiments show that the functionalized Ti scaffold significantly promotes osteogenesis in bone marrow mesenchymal stem cells(BMSCs)and angiogenesis in human umbilical vein endothelial cells(HUVECs)by activating the extracellular signal-regulated protein kinase(ERK)and HIF-1αsignaling pathways.After being implanted into a rat femoral condyle defect model,the functionalized Ti scaffold can induce in situ vascularized bone regeneration by orchestrating the two coupled processes of angio-genesis and osteogenesis.These findings indicate that the functionalized Ti scaffold has great potential in bone tissue regeneration and is a promising candidate for load-bearing bone defect repair.
基金supported by Bayer HealthCare Pharmaceuticals Inc.(57440)Department of Defense,CDMRP-KCRP(KC210132P1,USA)+2 种基金University of Texas MD Anderson Cancer CenterCancer Prevention and Research Institute of Texas(RP230160,USA)National Institutes of Health(P41EB023833,P30CA016672,USA).
文摘Radium-223(^(223)Ra)is a bone-seeking,alpha-particle-emitting radionuclide that is approved for the treatment of patients with metastatic prostate cancer and is currently being tested in clinical trials for primary and metastatic cancers to the bone.^(223)Ra accumulates in mineralized bone areas with high bone turnover,where its effects are confined within 100μm of the bone-marrow interface due to the short tissue penetrance of the alpha particles.A recent clinical study has shown a significantly increased fracture rate associated with the administration of^(223)Ra,mostly in tumor-free bones.Importantly,the biological mechanisms underlying this bone fragility remain unclear.In this work,we combined micro-computed tomography and mechanical studies with ex vivo spatial biology analysis based on 3D fluorescence microscopy to clarify the effects of^(223)Ra on bone and key bone stromal cell components.We found that^(223)Ra caused major trabecular bone loss with no detectable impact on cortical bone.In addition,^(223)Ra impaired osteoblast bone-forming activity,which was paralleled by a transient increase in osteoclast number and long-term adipocyte formation.Overall,these results suggest that the impact of^(223)Ra on bone health is orchestrated by multiple bone stromal cell components.^(223)Ra-mediated trabecular bone loss was prevented by administration of zoledronic acid,which should always be combined with^(223)Ra.
基金the National Natural Science Foundation of China(62174013,92265111,52302343)the funding Program of BIT(3180012212214,3180023012204,RCPT-20220029,XSQD6120220130).
文摘The bone repair niche,including the physiological and pathological microenvironment,is a complex system that interferes with various cellular/noncellular activities.Thus,a rational perspective of designing tunable biomaterials with the modulation of the bone microenvironment is in high demand in pre/clinical practice for the management of refractory bone defects in combination with severe bone diseases.Two-dimensional(2D)layered materials are emerging biomaterials for bone microenvironment engineering because of their inherent biocompatibility,osteo-inductivity,osteo-conductivity,optical properties,enzyme mimetics,and mechanical properties.In this study,we focus on the latest advances in developing 2D layered materials in bone regeneration,bone cancer therapies,bone-related infections eradication,and articular cartilage repair.In addition,the specific action mechanisms and design regimens of 2D-layered material-based nanoplatforms are clarified.Finally,the current challenges are discussed,and the key inspirations for further broadening the pre/clinical applications of 2D layered materials in orthopedic disorder therapy are proposed.
基金This work was supported the National Natural Science Foundation of China(Nos.81803097 and 81602727)the Natural Science Foundation of Shandong Province(No.ZR2017QH005).
文摘Bone metastasis is the leading cause of death in prostate cancer patients,for which there is currently no effective treatment.Since the bone microenvironment plays an important role in this process,attentions have been directed to the interactions between cancer cells and the bone microenvironment,including osteoclasts,osteoblasts,and bone stromal cells.Here,we explained the mechanism of interactions between prostate cancer cells and metastasis-associated cells within the bone microenvironment and further discussed the recent advances in targeted therapy of prostate cancer bone metastasis.This review also summarized the effects of bone microenvironment on prostate cancer metastasis and the related mechanisms,and provides insights for future prostate cancer metastasis studies.
基金This work was supported by National Natural Science Foundation of China.(No.82170960,81870769,51973243,52173150 and 82201098)Guangdong Basic and Applied Basic Research Foundation(No.2019A1515110379 and 2021A1515010782)the Shenzhen Basic Research Project(JCYJ20190807155801657).
文摘Recent evidence highlights multifaceted biological needs to recapitulate the bone microenvironment for bone regeneration.Neurotization has great potential for realizing multi-system modulations in bone tissue engineering(BTE).However,a neural strategy involving all the key bone repair steps temporally has not yet been reported.In this study,we reported the neural tissue engineering hydrogel-encapsulated Schwann cell-derived exosomes(SC Exo).This sustained-release SC Exo system prominently enhanced bone regeneration by promoting innervation,immunoregulation,vascularization,and osteogenesis in vivo.Moreover,the in vitro results further confirmed that this system significantly induced M2 polarization of macrophages,tube formation of HUVECs,and BMSCs osteogenic differentiation.Furthermore,BMSCs osteogenesis was promoted by upregulating the TGF-β1/SMAD2/3 signaling pathway.In summary,a novel cell-free and easily prepared SC Exo neural engineering was successfully developed to promote bone regeneration by orchestrating the entire bone healing microenvironment,which may provide a new strategy for tissue engineering and clinical treatment of bone defects.
基金supported by the Integration Project of NSFC Joint Fund for Regional Innovation and Development(U23A6008)the Key Programme of National Natural Science Foundation of China(81930067)+2 种基金the Youth Program of National Natural Science Foundation of China(82002316)the General Program of Natural Science Foundation of Chongqing(cstc2019jcyj-msxmX0176)the China Postdoctoral Science Foundation(2021MD703946).
文摘Osteoarthritis(OA)is a progressive degenerative joint sickness related with mechanics,obesity,ageing,etc.,mainly characterized by cartilage degeneration,subchondral bone damage and synovium inflammation.Coordinated mechanical absorption and conduction of the joint play significant roles in the prevalence and development of OA.Subchondral bone is generally considered a load-burdening tissue where mechanosensitive cells are resident,including osteocytes,osteoblast lineage cells,and osteoclast lineage cells(especially less concerned in mechanical studies).Mechano-signaling imbalances affect complicated cellular events and disorders of subchondral bone homeostasis.This paper will focus on the significance of mechanical force as the pathogenesis,involvement of various mechanical force patterns in mechanosensitive cells,and mechanobiology research of loading devices in vitro and in vivo,which are further discussed.Additionally,various mechanosensing structures(e.g.,transient receptor potential channels,gap junctions,primary cilia,podosome-associated complexes,extracellular vesicles)and mechanotransduction signaling pathways(e.g.,Ca^(2+) signaling,Wnt/β-catenin,RhoA GTPase,focal adhesion kinase,cotranscriptional activators YAP/TAZ)in mechanosensitive bone cells.Finally,we highlight potential targets for improving mechanoprotection in the treatment of OA.These advances furnish an integration of mechanical regulation of subchondral bone homeostasis,as well as OA therapeutic approaches by modulating mechanical homeostasis.
基金Supported by a grant from National Scaling Height Program, China (No. 95-zhuan-10)
文摘Objective： The aim of the study was to investigate the expression pattern of hematopoietic transcription factor GATA-1, -2 and -3 genes in leukemic bone marrow （BM） micreenvironment [including bone marrow stremal cells （BMSCs） and BM hematopoietic cells]. Methods： Mononuclear cells were isolated from BM of patients with acute myeloid leukemia （AML）, chronic myelogenous leukemia （CML）, or acute lymphoblasUc leukemia （ALL）. Adherent cells （BMSCs） and nonadherent ceils （BM hematopoietic cells） were collected after long-term culture in vitro. The semi-quantitative expression levels of GATA genes in the BMSCs or BM hematopoietic cells from patients with leukemia were analyzed by using RT-PCR-ELISA and com- pared with normal controls. Results： The expression level of GATA-1 gene in the BMSCs from CML group was significantly lower than that of the normal controls. The expression level of GATA-3 gene in the BMSCs from ALL was higher than that of the normal controls, but that from CML was lower than the normal controls. Dominant expression of GATA-3 gene was found in the normal BM hematopoietic cells. The dominant expression of GATA-2 gene was found in the normal BMSCs and the BMSCs from CML, whereas the dominant expression of GATA-3 gene was detected in the BMSCs from AML. Conclusion： GATA-1, -2 and -3 genes might play a role in hematopoiesis regulation in leukemia, and the changes of expression pattern of GATA genes might influence the hematopoiesis in BM microenvironment and relate to the pathogenesis and development of leukemia.
基金Project supported by the National Natural Science Foundation of China(21807023)the Natural Science Foundation of Hebei Province(B2019201449,H2019201466)+2 种基金the Hebei Province“Three Three Three Talents Program”(A202003001)the Government Guided Local Science and Technology Fundations of Hebei Province(216Z2403G)the Priority Strategy Project of the Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education(ts2020003)。
文摘With lanthanum(La) in agriculture, medicine, and the chemical industry, La shows accumulation in the body, especially in the bone, because of its similar structure to calcium. Moreover, La has a direct role in bone formation regulating osteoblasts and osteoclasts. Nevertheless, bone formation is complex under the regulation of osteogenesis, osteoclastogenesis, and angiogenesis in the bone microenvironment. It is difficult to comprehensively understand the regulation of bone homeostasis from a single kind of cell.Herein, some bone microenvironment-related cells and mouse calvaria culture models were used to study the regulatory effect of La-based compound-lanthanum nitrate(La(NO_(3))_(3)) on bone formation.La(NO_(3))_(3) has good biological safety, and the osteogenic differentiation is significantly increased under La(NO_(3))_(3) treatment for bone marrow mesenchymal stem cells(BMMSC). In contrast, the differentiation,maturation, and bone erosion ability of osteoclasts are significantly decreased. Meanwhile, the angiogenesis ability of human umbilical vein endothelial cells(HUVEC) is significantly promoted when treated with La(NO_(3))_(3). Furthermore, bone metabolism and angiogenesis are improved under La(NO_(3))_(3) treatment in the calvaria ex vivo culture model and BMMSC-HUVEC co-culture system. These results suggest that La has the beneficial effect of promoting bone metabolism and improving bone formation in the bone microenvironment.
基金ThisprojectwassupportedbyagrantfromtheNationalNatu ralScienceFoundationofChina (No .39870 92 6 )
文摘To study the expression of the bFGF and its receptor in the mouse bone marrow by treatment with acute radioactive injury and Ligustrazine, 56 mice were divided into 3 groups: normal group, radiation injured group and Ligustrazine group. After irradiation by 6.0 Gy 60 Co γ ray, each mouse was orally given 0.1 ml Ligustrazine twice a day for 13 days in Ligustrazine group, and each mouse in radiation injured group was orally given equal amount of saline. On the 3rd, 7th, 14th day after irradiation, bone marrow mono nuclear cells (BMMNC) were counted, and the expression levels of bFGF and bFGFR in bone marrow were evaluated by immunohistochemistry and flow cytometry analysis respectively. On the 3rd, 7th, 14th day after irradiation, expression of bFGF in bone marrow were significantly lower than in normal group ( P <0.05 or P <0.01). Expressions of bFGF and bFGFR were much higher in Ligustrazine treated group than that in the control group ( P <0.05 or P <0.01). Ligustrazine potentiate the expression of bFGF and bFGFR in bone marrow MNC to recover the bone marrow hematopoiesis inductive microenvironment, which is one of the mechanisms by which Ligustrazine rebuild the bone marrow hematopoiesis after acute radioactive injury.
基金Supported by The“Instituto de Salud Carlos III,No.PI22/00264A Predoctoral Program in Biomedicine from The University of Cantabria and The Instituto de Investigación Valdecilla-IDIVAL(Alberto González-González and Daniel García-Sánchez),No.PREVAL19/02,and No.PREVAL20/01“Investigo Program”,part of the“Plan Nacional de Recuperación,Transformación y Resiliencia”from The Spanish Government(Mónica del Dujo-Gutiérrez).
文摘Multiple myeloma(MM)is a hematological malignancy characterized by the accumulation of immunoglobulin-secreting clonal plasma cells at the bone marrow(BM).The interaction between MM cells and the BM microenvironment,and specifically BM mesenchymal stem cells(BM-MSCs),has a key role in the pathophysiology of this disease.Multiple data support the idea that BM-MSCs not only enhance the proliferation and survival of MM cells but are also involved in the resistance of MM cells to certain drugs,aiding the progression of this hematological tumor.The relation of MM cells with the resident BM-MSCs is a two-way interaction.MM modulate the behavior of BM-MSCs altering their expression profile,proliferation rate,osteogenic potential,and expression of senescence markers.In turn,modified BM-MSCs can produce a set of cytokines that would modulate the BM microenvironment to favor disease progression.The interaction between MM cells and BM-MSCs can be mediated by the secretion of a variety of soluble factors and extracellular vesicles carrying microRNAs,long non-coding RNAs or other molecules.However,the communication between these two types of cells could also involve a direct physical interaction through adhesion molecules or tunneling nanotubes.Thus,understanding the way this communication works and developing strategies to interfere in the process,would preclude the expansion of the MM cells and might offer alternative treatments for this incurable disease.
基金Supported by the "Ninth Five" Obligatory Budget of PLA. No. 96L045
文摘Objective: To explore the effect of gamma irradiation on nuclear factor-kappa B in cultured bone marrow stromal cells. Methods: Immunocytochemistry, Western blot and electrophoretic mobility shift assay (EMSA) were used. Results: The expression of NF-kB in cultured mouse bone marrow stromal cells (BM-SCs) on the level of protein was elevated after exposure to 60Co in the dosage of 8. 0 Gy with the use of im-munocytochemistry and Western blot. The activity of nuclear factor-kappa B in cultured BMSCs was significantly increased after exposure to gamma irradiation by using EMSA. The activity peak was at the 4th h after irradiation. Conclusion: Our results suggest that the activation of nuclear factor-kappa B in the BMSCs after irradiation may be involved in the protection of BMSCs against apoptosis and in the recovery of hematopoiesis after radiation.
基金the National Natural Science Foundation of China(No.82372406)Hubei Provincial Natural Science Foundation(No.2025AFB872)+1 种基金the Fundamental Reseach Funds for the Central Universities(No.YCJJ20241103)the Open Foundation of Hubei Key Laboratory of Biological Targeted Therapy(No.202412)。
文摘Diabetic conditions impair bone regeneration due to dysregulated macrophage polarization and inflammatory imbalance.Current therapies often fail to address systemic immune homeostasis.Herein,a bone-targeted nanoplatform(abbreviated as AgSr-MSNs)is engineered to scavenge excess nitric oxide(NO)and respond to the acidic diabetic microenvironment based on upregulated inducible nitric oxide synthase(iNOS)expression in M1 macrophages residing within both the diabetic bone marrow and localized osteolytic regions in our study.The system integrates silver sulfide quantum dots(Ag2S QDs)and Sr^(2+)into mesoporous silica nanoparticles(MSNs),encapsulated with rhodamine/β-cyclodextrin and surface-modified with alendronate for bone-specific targeting.Under near-infrared(NIR)irradiation,the nanoparticles induce macrophage repolarization toward M2 phenotypes through JAK/STAT signaling pathway,followed by upregulating anti-inflammatory mediators(TGF-β,PD-L1)and tissue-regenerative factors(BMP-2/4,VEGF-B),while suppressing pro-inflammatory cytokines(CCR2,S100A4).This dual NO/pH-responsive platform synergistically mitigates inflammatory dysregu-lation,enhances osteogenesis,and promotes angiogenesis.In diabetic models,systemic administration with NIRmediated mild hyperthermia reduces CD86^(+)macrophages and TNF-αlevels while elevating CD206^(+)macrophages locally and systemically.Concurrently,it boosts CD31,Runx2,and osteocalcin(OCN)expression levels at defect sites,indicating restored vascularization and osteogenesis.This strategy addresses the pathological triad of diabetic osteopathy-chronic inflammation,vascular insufficiency,and osteogenic impairment-providing a translatable nanotherapeutic paradigm for metabolic bone disorders.
基金funded by Umberto Veronesi Foundation and Pfizer Global Medical Grants(grant tracking number 75340503)supported by the European Research Council under the European Union’s Horizon 2020 research and innovation pro-gram(grant agreement number 817997)+1 种基金Associazione Italiana Ricerca sul Cancro(grant IG25739)supported in part by Italian Ministry of Health,current research IRCCS.
文摘The role of bone marrow(BM)compensatory response in autoimmune hemolytic anemias(AIHAs)is emerging and inadequate reticulocytosis has been associated with more severe disease and adverse outcomes.However,few is known about the BM immunologic microenvironment composition in these diseases.Here we investigated BM features in a large cohort of 97 patients with autoimmune hemolytic anemia(AIHA)and observed a high prevalence of hypercellularity,dyserythropoiesis,reticulin fibrosis,and T-cell infiltration(65%,29%,76%,and 69%of patients,respectively).These findings were associated with inadequate bone marrow compensation,more severe anemia at onset,and need of multiple treatments.In a subset of warm type AIHA patients we investigated BM microenvironment by single-cell RNA sequencing.We found distinct immune cell profiles across disease stages(diagnosis,remission,relapse).In particular,upregulation of inflammatory response pathways was noted in CD8+,CD4+,and monocyte subsets during relapse compared to diagnosis and remission.Moreover,by single-cell TCR sequencing,we found small T cell clones at diagnosis that may either disappeared or expanded at remission.Disappearing clones exhibited a naive CD8+phenotype and were more likely to respond to glucocorticoid treatment.Expanding clones showed upregulation of cytotoxic T cell markers and may play a role in the transition to a chronic/relapsing phase.Finally,cytokine gene expression differed across disease phases.At relapse,pro-inflammatory cytokines such as TNF-alpha,IL-1,and IL-6 were upregulated in CD4+and CD8+T cells,while TGF-beta was downregulated,potentially in an attempt to counteract the transition to chronic phase.This is the largest study evaluating BM histology and clinical characteristics,and the first evaluation of BM microenvironment by single-cell RNA sequencing in AIHA.We showed a complex scenario encompassing T-cell infiltration,clonality,and up/down-regulation of cytokine genes,associated with a more severe and relapsing disease.
文摘Epithelial-mesenchymal transition （EMT） in cancer describes the phenotypic and behavioral changes of cancer cells from indolent to virulent forms with increased migratory, invasive and metastatic potential. EMT can be induced by soluble proteins like transforming growth factor β1 （TGFβ1） and transcription factors including Snail and Slug. We utilized theARCaPE/ARCaPM prostate cancer progression model and LNCaP clones stably overexpressing Snail to identify novel markers associated with EMT. Compared to ARCaPE cells, the highly tumorigenic mesenchymal ARCaPM and ARCaPM1 variant cells displayed a higher incidence of bone metastasis after intracardiac administration in SCID mice. ARCaPM and ARCaPM1 expressed mesenchymal stromal markers of vimentin and N-cadherin in addition to elevated levels of Receptor Activator of NF-κB Ligand （RANKL）. We observed that both epidermal growth factor （EGF） plus TGFβ1 treatment and Snail overexpression induced EMT in ARCaPE and LNCaP cells, and EMT was associated with increased expression of RANKL protein. Finally, we determined that the RANKL protein was functionally active, promoting osteoclastogenesis in vitro. Our results indicate that RANKL is a novel marker for EMT during prostate cancer progression. RANKL may function as a link between EMT, bone turnover, and prostate cancer skeletal metastasis.
基金funded by National Natural Science Foundation of China(Grant No.82060311)the Key Research and Development Program of Guangxi(Grant No.GuikeAB23026001)Sichuan Provincial Science Foundation for Distinguished Young Scholars(Grant No.2024NSFJQ0048).
文摘Critical-sized bone defects represent a significant clinical challenge due to their inability to undergo spontaneous regeneration,necessitating graft interventions for effective treatment.The development of tissue-engineered scaffolds and regenerative medicine has made bone tissue engineering a highly viable treatment for bone defects.The physical and biological properties of nanocomposite biomaterials,which have optimized structures and the ability to simulate the regenerative microenvironment of bone,are promising for application in the field of tissue engineering.These biomaterials offer distinct advantages over traditional materials by facilitating cellular adhesion and proliferation,maintaining excellent osteoconductivity and biocompatibility,enabling precise control of degradation rates,and enhancing mechanical properties.Importantly,they can simulate the natural structure of bone tissue,including the specific microenvironment,which is crucial for promoting the repair and regeneration of bone defects.This manuscript provides a comprehensive review of the recent research developments and applications of structure-optimized and microenvironment-inspired nanocomposite biomaterials in bone tissue engineering.This review focuses on the properties and advantages these materials offer for bone repair and tissue regeneration,summarizing the latest progress in the application of nanocomposite biomaterials for bone tissue engineering and highlighting the challenges and future perspectives in the field.Through this analysis,the paper aims to underscore the promising potential of nanocomposite biomaterials in bone tissue engineering,contributing to the informed design and strategic planning of next-generation biomaterials for regenerative medicine.
基金supported by the National Natural Science Foundation of China(82230071,82172098,82472479,82302397)Shanghai Committee of Science and Technology(23141900600).
文摘Given the limitations of allogeneic and artificial bone grafts,bone organoids have attracted extensive attention for their physiological properties that closely resemble natural bone,offering great potential to bone recon-struction for critical-sized bone defects.Although early-stage bone organoids such as osteo-callus organoids and woven bone organoids have been reported,functional bone organoids with vascularization and mineralization are currently unavailable due to the lack of bone-mimicking matrix and dynamic culture systems suitable for the long-term cultivation of mature bone organoids.Herein,a novel engineered bionic matrix hydrogels with multifunctional components and double network structure are developed by incorporating calcium phosphate oligomers(CPO)into a combination of bone-derived decellularized extracellular matrix(ECM)and salmon-derived deoxyribonucleic acid(DNA)via photo-crosslinking and dynamic self-assembly strategies.This kind of bionic matrix hydrogels facilitate recruitment,proliferation,osteogenesis and angiogenesis of bone marrow mesenchymal stromal cells(BMSCs).More importantly,vascularized and mineralized bone organoids are sequentially constructed using BMSCs-loaded engineered bionic matrix hydrogels via in vitro dynamic culture and in vivo heterotopic ossification.Meanwhile,this kind of engineered bionic matrix are capable of achieving efficient bone repair for cranial defect.These findings suggest that engineered bionic matrix hydrogels combined with such dynamic culture system,providing a promising strategy for functional bone organoids construction.
基金National Natural Science Foundation of China(82272468,52173146)the Special Fund for Industrialization of Science and Technology Cooperation between Jilin Province and Chinese Academy of Sciences(2022SYHZ0022)the Jilin Provincial science and technology development program(No.20230401089YY)。
文摘Using bone tissue engineering strategies to achieve bone defect repair is a promising modality.However,the repair process outcomes are often unsatisfactory.Here we properly designed a multi-functional microsphere system,which could deliver bioactive proteins under the dual response of ultrasound and microenvironment,release microenvironment-responsive products on demand,reverse bone injury microenvironment,regulate the immune microenvironment,and achieve excellent bone defect treatment outcomes.In particular,the MnO_(2) introduced into the poly(lactic-co-glycolic acid)(PLGA)microspheres during synthesis could consume the acid produced by the degradation of PLGA to protect bone morphogenetic protein-2(BMP-2).More importantly,MnO_(2) could consume reactive oxygen species(ROS)and produce Mn^(2+)and oxygen(O_(2)),further promoting the repair of bone defects while reversing the microenvironment.Moreover,the reversal of the bone injury microenvironment and the depletion of ROS promoted the polarization of M1 macrophages to M2 macrophages,and the immune microenvironment was regulated.Notably,the ultrasound(US)irradiation used during treatment also allowed the on-demand release of microenvironment-responsive products.The multi-functional microsphere system combines the effects of on-demand delivery,reversal of bone injury microenvironment,and regulation of the immune microenvironment,providing new horizons for the clinical application of protein delivery and bone defect repair.
基金supported by the National Natural Science Foundation of China(NSFC)(Nos.81902189,81772354,82002303,31570980)Clinical Innovation Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory(2018GZR0201001)+6 种基金National Key Research and Development Plan(2018YFC1105103)Research Grant Council General Research Funds(RGC GRF)(17214516)Shenzhen Science and Technology Innovation Funding(JCYJ20160429190821781 and JCYJ2016429185449249)Science Technology Project of Guangzhou City(201804010185)Science and Technology Innovation Project of Foshan City(1920001000025)Scientific Research Foundation of PEKING UNIVERSITY SHENZHEN HOSPITAL KYQD(2021064)National Young Thousand-Talent Scheme to Zhang Zhi-Yong.
文摘Regardless of the advancement of synthetic bone substitutes,allograft-derived bone substitutes still dominate in the orthopaedic circle in the treatments of bone diseases.Nevertheless,the stringent devitalization process jeopardizes their osseointegration with host bone and therefore prone to long-term failure.Hence,improving osseointegration and transplantation efficiency remains important.The alteration of bone tissue microenvironment(TME)to facilitate osseointegration has been generally recognized.However,the concept of exerting metal ionic cue in bone TME without compromising the mechanical properties of bone allograft is challenging.To address this concern,an interfacial tissue microenvironment with magnesium cationc cue was tailored onto the gamma-irradiated allograft bone using a customized magnesium-plasma surface treatment.The formation of the Mg cationic cue enriched interfacial tissue microenvironment on allograft bone was verified by the scanning ion-selective electrode technique.The cellular activities of human TERT-immortalized mesenchymal stem cells on the Mg-enriched grafts were notably upregulated.In the animal test,superior osseointegration between Mg-enriched graft and host bone was found,whereas poor integration was observed in the gamma-irradiated controls at 28 days post-operation.Furthermore,the bony in-growth appeared on magnesium-enriched allograft bone was significant higher.The mechanism possibly correlates to the up-regulation of integrin receptors in mesenchymal stem cells under modified bone TME that directly orchestrate the initial cell attachment and osteogenic differentiation of mesenchymal stem cells.Lastly,our findings demonstrate the significance of magnesium cation modified bone allograft that can potentially translate to various orthopaedic procedures requiring bone augmentation.
文摘Bone marrow(BM)microenvironment regulates and supports the production of blood cells which are necessary to maintain homeostasis.In analogy to normal hematopoiesis,leukemogenesis is originated from leukemic stem cells(LSCs)which gives rise to more differentiated malignant cells.Leukemia cells occupy BM niches and reconstruct them to support leukemogenesis.The abnormal BM niches are the main sanctuary of LSCs where they can evade chemotherapy-induced death and acquire drug resistance.In this review,we focus on the protective effects of BM niche cells on acute lymphoblastic leukemia cells.
