Chinese dwarf cherry(Cerasus humilis)is a fruit unique to China,which is considered to have osteoprotective effects.However,no systematic experimental characterization was available.In this study,the osteoprotective a...Chinese dwarf cherry(Cerasus humilis)is a fruit unique to China,which is considered to have osteoprotective effects.However,no systematic experimental characterization was available.In this study,the osteoprotective activity and mechanism of Chinese dwarf cherry polyphenol extract(OPE)was studied.In vitro,OPE stimulated the alkaline phosphatase activity in the early differentiation stage,increased the osteocalcin level in the middle differentiation stage,and induced the formation of more bonemineralized nodules in the late osteogenic stage.In vivo,OPE improved cancellous bone structure and maximum load of the femur in ovariectomized(OVX)rats.The balance between bone formation and resorption was regulated.Oxidative stress levels in the peripheral blood,liver and femur were reduced.OPE alleviated the disturbance in energy metabolism,muscle development,and muscle regulation-related signaling pathways caused by OVX and activated the calcium/adenosine monophosphate-activated protein kinase signaling pathway.Therefore,OPE is a potential dietary supplement for the prevention and treatment of osteoporosis.展开更多
Amyloid beta(AB)peptide 40 enhances the activation of receptor for advanced glycation end products(RAGE)in immune-inflammatory diseases.RAGE exhibits several ffects in the setting of numerous cardiovascular events.We ...Amyloid beta(AB)peptide 40 enhances the activation of receptor for advanced glycation end products(RAGE)in immune-inflammatory diseases.RAGE exhibits several ffects in the setting of numerous cardiovascular events.We bypothesized that the Aβ40/RAGE pathway is involved in the osteoblastic differentiation of the valvular interstitial cell(VIC)phenotype,and RAGE knockout intervention could reduce the calcification of aortic valve interstitial cells(AVICs)by inhibiting the extracellular-regulated kinase1/2(ERK 1/2)/nuclear factor kappa-B(NF-kB)signaling pathway.To test this hypothesis,the activation of AB40/RAGE pathway in human calcific AVs was evaluated with immunohistochemical staining.Cultured calcific VIC models were used in vitro.The VICs were stimulated using Aβ40,with or without RAGE small interfering ribonucleic acid(siRNA),and ERK1/2 and NF-κB inhibitors for analysis.Our data revealed that AB40 induced the ERK 1/2/NF-κB signaling pathway and osteoblastic differentiation of AVICs via the RAGE pathway in vitro.展开更多
Biointerface design can greatly influence cell behavior. Therefore, in this study we examined the effects of three surface characteristics, roughness, chemistry, and wettability, on osteoblastic cell differentiation. ...Biointerface design can greatly influence cell behavior. Therefore, in this study we examined the effects of three surface characteristics, roughness, chemistry, and wettability, on osteoblastic cell differentiation. We examined osteoblastic differentiation on titanium (Ti) samples with four levels of roughness (average roughness: 148.6 ± 23.1, 42 ± 6.2, 14.3 ± 5.5, 7.2 ± 1.6 nm) with or without a nanolayer coating of polydopamine (PDA). In vitro osteogenic differentiation was evaluated by quantifying alkaline phosphatase (AP) activity of human fetal preosteoblastic (hFOB 1.19) cells. The change in surface chemistry of Ti samples as a result of PDA coating was assessed by XPS analysis and water contact angle measurement. Results demonstrated that PDA treated samples were more hydrophilic, compared to untreated samples, and this was substrate roughness independent. Moreover, with the exception of the substrate with an oriented texture of surface nanotopography (RTi-4), the presence of a PDA nanolayer increased AP activity independent of substrate roughness. Our results suggest that surface chemistry and wettability, induced by a PDA nanolayer coating, had a greater effect on osteoblastic differentiation than did surface roughness.展开更多
The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis.Nuclear receptors(NRs)are now understood to be crucial in bone physiology and pathology.However,...The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis.Nuclear receptors(NRs)are now understood to be crucial in bone physiology and pathology.However,the function of the Farnesoid X receptor(FXR),a member of the NR family,in regulating bone homeostasis remains incompletely understood.In this study,in vitro and in vivo models revealed delayed bone development and an osteoporosis phenotype in mice lacking FXR in bone marrow mesenchymal stem cells(BMSCs)and osteoblasts due to impaired osteoblast differentiation.Mechanistically,FXR could stabilize RUNX2 by inhibiting Thoc6-mediated ubiquitination,thereby promoting osteogenic activity in BMSCs.Moreover,activated FXR could directly bind to the Thoc6 promoter,suppressing its expression.The interaction between RUNX2 and Thoc6 was mediated by the Runt domain of RUNX2 and the WD repeat of Thoc6.Additionally,Obeticholic acid(OCA),an orally available FXR agonist,could ameliorate bone loss in an ovariectomy(OVX)-induced osteoporotic mouse model.Taken together,our findings suggest that FXR plays pivotal roles in osteoblast differentiation by regulating RUNX2 stability and that targeting FXR may be a promising therapeutic approach for osteoporosis.展开更多
Neural EGFL-like 2(NELL2)is a secreted protein known for its regulatory functions in the nervous and reproductive systems,yet its role in bone biology remains unexplored.In this study,we observed that NELL2 was dimini...Neural EGFL-like 2(NELL2)is a secreted protein known for its regulatory functions in the nervous and reproductive systems,yet its role in bone biology remains unexplored.In this study,we observed that NELL2 was diminished in the bone of aged and ovariectomized(OVX)mice,as well as in the serum of osteopenia and osteoporosis patients.In vitro loss-of-function and gain-offunction studies revealed that NELL2 facilitated osteoblast differentiation and impeded adipocyte differentiation from stromal progenitor cells.In vivo studies further demonstrated that the deletion of NELL2 in preosteoblasts resulted in decreased cancellous bone mass in mice.Mechanistically,NELL2 interacted with the FNI-type domain located at the C-terminus of Fibronectin 1(Fn1).Moreover,we found that NELL2 activated the focal adhesion kinase(FAK)/AKT signaling pathway through Fn1/integrinβ1(ITGB1),leading to the promotion of osteogenesis and the inhibition of adipogenesis.Notably,administration of NELL2-AAV was found to ameliorate bone loss in OVX mice.These findings underscore the significant role of NELL2 in osteoblast differentiation and bone homeostasis,suggesting its potential as a therapeutic target for managing osteoporosis.展开更多
Carcinosarcomas are rare,malignant,biphasic tumors simultaneously comprising carcinoma and sarcoma in a single tumor.We present an extremely rare case of gastric carcinosarcoma with an osteoblastic component that dras...Carcinosarcomas are rare,malignant,biphasic tumors simultaneously comprising carcinoma and sarcoma in a single tumor.We present an extremely rare case of gastric carcinosarcoma with an osteoblastic component that drastically changed its shape within 2 mo.A 59-year-old male patient presented to the emergency outpatient unit with a complaint of black stool.Gastrointestinal endoscopy showed an ulcerated mass in the cardia of the lesser curvature of the stomach.Biopsy specimens revealed only adenocarcinoma.Two months later,the ulcerated lesion drastically changed its shape into an exophytic tumor.Total gastrectomy was performed.In the resected specimen,the gastric tumor contained both adenocarcinoma and sarcoma components with lace-like osteoid.The patient died 7 mo after the operation,and an autopsy was performed.In the autopsy,widespread metastases were present in the liver,lung,lymph nodes and peritoneum.In this report,we describe a case of gastric carcinosarcoma and presume its tumorigenesis based on the autopsy findings.展开更多
In the recent two decades, it has been well elucidated that receptor activator of nuclear factor-κB ligand （RANKL; also known as TNFSF11） binding to its receptor RANK （also known as TNFRSF11A） drives osteoclast d...In the recent two decades, it has been well elucidated that receptor activator of nuclear factor-κB ligand （RANKL; also known as TNFSF11） binding to its receptor RANK （also known as TNFRSF11A） drives osteoclast development as the crucial signaling pathway.;However, accumulating evidence also implies that展开更多
Age-related osteoporosis is associated with the reduced capacity of bone marrow mesenchymal stem cells （BMSCs） to differentiate into osteoblasts instead of adipocytes. However, the molecular mechanisms that decide t...Age-related osteoporosis is associated with the reduced capacity of bone marrow mesenchymal stem cells （BMSCs） to differentiate into osteoblasts instead of adipocytes. However, the molecular mechanisms that decide the fate of BMSCs remain unclear. In our study, microRNA-23a, and microRNA-23b （miR-23a/b） were found to be markedly downregulated in BMSCs of aged mice and humans. The overexpression of miR-23a/b in BMSCs promoted osteogenic differentiation, whereas the inhibition of miR-23a/b increased adipogenic differentiation. Transmembrane protein 64 （Tmem64）, which has expression levels inversely related to those of miR-23a/b in aged and young mice, was identified as a major target of miR-23a/b during BMSC differentiation. In conclusion, our study suggests that miR-23a/b has a critical role in the regulation of mesenchymal lineage differentiation through the suppression of Tmem64.展开更多
Adipose derived stem cells represent a readily available source of adult stem cells for various biomedical applications. In this study, the proliferation and osteogenic differentiation potential of lanthanum nitrate（...Adipose derived stem cells represent a readily available source of adult stem cells for various biomedical applications. In this study, the proliferation and osteogenic differentiation potential of lanthanum nitrate（La3＋） on human adipose derived mesenchymal stem cells（hADSCs） were investigated for the first time and compared with that of dexamethasone（Dex）. Our results provided evidence that La3＋ at 50 μmol/L concentration promoted proliferation of hADSCs upto 2.4 fold when treated for 21 d in DMEM medium. Treatment of hADSCs with La3＋ containing osteogenic induction medium（α-MEM with ascorbic acid and β-glycerophosphate） for 7 d resulted in higher calcium deposition than that in the presence of Dex（0.1 μmol/L） as shown by Alizarin red S and von Kossa staining. Scanning electron micrographs also showed more extracellular matrix mineralization in the presence of La3＋. After 7 d of treatment with La3＋（10 μmol/L） the expression of RunX2, osteopontin（OP） and osteocalcin（OC） increased 3.4, 5.5 and 2.7 fold respectively. Our results provided evidence that in the presence of La3＋ osteogenic differentiation occurred earlier than that in the presence of Dex.展开更多
99mTc-Methylene diphosphonate （99mTc-MDP） is widely used in clinical settings to detect bone abnormalities. However, the mechanism of 99mTc-MDP uptake in bone is not well elucidated. In this study, we utilized a mou...99mTc-Methylene diphosphonate （99mTc-MDP） is widely used in clinical settings to detect bone abnormalities. However, the mechanism of 99mTc-MDP uptake in bone is not well elucidated. In this study, we utilized a mouse tibia injury model, single-photon emission computed tomography （gamma scintigraphy or SPECT）, ex vivo micro-computed tomography, and histology to monitor 99mTc-MDP uptake in injury sites during skeletal healing. In an ex vivo culture system, calvarial cells were differentiated into osteoblasts with osteogenic medium, pulsed with 99mTc-MDP at different time points, and quantitated for 99mTc-MDP uptake with a gamma counter. We demonstrated that 99mTc-MDP uptake in the injury sites corresponded to osteoblast generation in those sites throughout the healing process. The 99mTc-MDP uptake within the injury sites peaked on day 7 post-injury, while the injury sites were occupied by mature osteoblasts also starting from day 7. ~mTc-MDP uptake started to decrease 14 days post-surgery, when we observed the highest level of bony tissue in the injury sites. We also found that 99mTc-MDP uptake was associated with osteoblast maturation and mineralization in vitro. This study provides direct and biological evidence for 99mTc-MDP uptake in osteoblasts during bone healing in vivo and in vitro.展开更多
Indian hedgehog （Ihh） is an essential signal that regulates endochondral bone development. We have previously shown that Wnt7b promotes osteoblast differentiation during mouse embryogenesis, and that its expression ...Indian hedgehog （Ihh） is an essential signal that regulates endochondral bone development. We have previously shown that Wnt7b promotes osteoblast differentiation during mouse embryogenesis, and that its expression in the perichondrium is dependent on Ihh signaling. To test the hypothesis that Wnt7b may mediate some aspects of Ihh function during endochondral bone development, we activated Wnt7b expression from the R26-Wnt7b allele with Col2-Cre in the Ihh-/- mouse. Artificial expression of Wnt7b rescued vascularization of the hypertrophic cartilage in the Ihh-/- mouse, but failed to restore orthotopic osteoblast differentiation in the perichondrium. Similarly, Wnt7b did not recover Ihh-dependent perichondral bone formation in the Ihh-/-; Gli3-/- embryo. Interestingly, Wnt7b induced bone formation at the diaphyseal region of long bones in the absence of Ihh, possibly due to increased vascularization in the area. Thus, Ihh-dependent expression of Wnt7b in the perichondrium may contribute to vascularization of the hypertrophic cartilage during endochondral bone development.展开更多
Titanium （Ti） nanorods fabricated using selective corrosion of Ti substrate by anodic technology show better biocompatibility with pre-osteoblast cells. The current study investigated the response of the murine pre-...Titanium （Ti） nanorods fabricated using selective corrosion of Ti substrate by anodic technology show better biocompatibility with pre-osteoblast cells. The current study investigated the response of the murine pre-osteoblast cell MCST3-E1 on Ti nanorod topography and untreated Ti surfaces by means of examination of the morphology and osteogenic differentiation responsible for the pre-osteoblast reaction. The morphology of MCST3-E1 cells was observed using scanning electron microscopy, and alkaline phosphatase （ALP） activity was measured using a colorimetric assay after incubation for 7, 14, and 21 days. The expression of three osteogenic differentiation markers including ALP, osteocalcin （OCN）, and collagen type 1A1 （COL1A1） and two transcription factors including runt related transcription factor 2 （Runx2） and osterix （Osx） at different time points was detected using real-time polymerase chain reaction analysis in both groups. Osx was used to confirm the protein level. The results showed that Ti nanorod surfaces provided prolonged higher levels of ALP activity compared with unmodified Ti surface on the 14th and 21st days. Gene expression analysis of ALP, OCN, and COL1A1 showed significant upregulation with modified nanorod topography after incubation for 14 and 21 days. Osteogenic transcription factors of Runx2 and Osx exhibited changes consistent with the osteogenic differentiation markers, and this may contribute to the persistently active differentiation of MC3T3-E1 cells in the Ti nanorod group. These results demonstrated that the current nanostructured surface may be considered bioadaptive topography to control cellular behaviors and osteoblast differentiation. The in vivo performance and applicability are further required to investigate osseointegration between implant and host bone in the early stages for prevention of aseptic implant loosening.展开更多
While both induction culture media and matrix have been reported to regulate the stem cell fate,little is known about which factor plays a more decisive role in directing the MSC differentiation lineage as well as the...While both induction culture media and matrix have been reported to regulate the stem cell fate,little is known about which factor plays a more decisive role in directing the MSC differentiation lineage as well as the underlying mechanisms.To this aim,we seeded MSCs on HA-collagen and HA-synthetic hydrogel matrixes,which had demonstrated highly different potentials toward osteoblastic and chondrocytic differentiation lineages,respectively,and cultured them with osteogenic,chondrogenic and normal culture media,respectively.A systematic comparison has been carried out on the effects of induction media and matrix on MSC adhesion,cytoskeleton organization,proliferation,and in particular differentiation into the osteoblastic and chondrocytic lineages.The results demonstrated that the matrix selection had a much more profound effect on directing the differentiation lineage than the induction media did.The strong modulation effect on the transcription activities might be the critical factor contributing to the above observations in our study,where canonical Wnt-b-Catenin signal pathway was directly involved in the matrix-driven osteoblastic differentiation.Such findings not only provide a critical insight on natural cellular events leading to the osteoblastic and chondrocytic differentiations,but also have important implications in biomaterial design for tissue engineering applications.展开更多
Objective:To investigate the effect of an aqueous extract of Protaetia brevitarsis(AEPB)on osteogenesis using preosteoblast MC3T3-E1 cells and zebrafish larvae.Methods:Flow cytometric analysis was used to measure the ...Objective:To investigate the effect of an aqueous extract of Protaetia brevitarsis(AEPB)on osteogenesis using preosteoblast MC3T3-E1 cells and zebrafish larvae.Methods:Flow cytometric analysis was used to measure the cytotoxicy.Alkaline phosphatase activity was detetmined using p-nitrophenyl phosphate as a substrate.Calcium deposition was detected using alizarin red staining along with osteogenic marker expression in preosteoblast MC3T3E1 cells.In addition,vertebral formation in zebrafish larvae was detected using calcein staining and osteogenic gene expression.Results:AEPB highly promoted the expression of osteogenic markers including runt-related transcription factor 2,osterix,and alkaline phosphatase,along with elevated levels of mineralization in MC3T3-E1 cells.Moreover,AEPB accelerated vertebral formation in zebrafish larvae accompanied by upregulated expression of osteogenic genes.FH535,an inhibitor of Wnt/β-catenin,suppressed AEPB-induced osteogenic gene expression and vertebral formation,indicating that AEPB stimulates osteogenesis by activating the Wnt/β-catenin signaling pathway.Conclusions:AEPB stimulates osteoblast differentiation and bone formation by activatingβ-catenin.Therefore,AEPB is a promising material that induces osteogenesis,and is useful for the treatment of bone resorption diseases.展开更多
Since 3D printed hard materials could match the shape of bone,cell survival and fate determination towards osteoblasts in such materials have become a popular research target.In this study,a scaffold of hardmaterial f...Since 3D printed hard materials could match the shape of bone,cell survival and fate determination towards osteoblasts in such materials have become a popular research target.In this study,a scaffold of hardmaterial for 3D fabrication was designed to regulate developmental signal(Notch)transduction guiding osteoblast differentiation.We established a polycaprolactone(PCL)and cell-integrated 3D printing system(PCI3D)to reciprocally print the beams of PCL and cell-laden hydrogel for a module.This PCI3D module holds good cell viability of over 87%,whereas cells show about sixfold proliferation in a 7-day culture.The osteocytic MLO-Y4 was engineered to overexpress Notch ligand Dll4,making up 25%after mixing with 75%stromal cells in the PCI3D module.Osteocytic Dll4,unlike other delta-like family members such as Dll1 or Dll3,promotes osteoblast differentiation and themineralization of primary mouse and a cell line of bone marrow stromal cells when cultured in a PCI3D module for up to 28 days.Mechanistically,osteocytic Dll4 could not promote osteogenic differentiation of the primary bone marrow stromal cells(BMSCs)after conditional deletion of the Notch transcription factor RBPjκby Cre recombinase.These data indicate that osteocytic Dll4 activates RBPjκ-dependent canonical Notch signaling in BMSCs for their oriented differentiation towards osteoblasts.Additionally,osteocytic Dll4 holds a great potential for angiogenesis in human umbilical vein endothelial cells within modules.Our study reveals that osteocytic Dll4 could be the osteogenic niche determining cell fate towards osteoblasts.This will open a new avenue to overcome the current limitation of poor cell viability and low bioactivity of traditional orthopedic implants.展开更多
The present work focused on developing an innovative composite material by reinforcing polymer matrix with highly porous activated charcoal. Polyvinyl alcohol-activated charcoal（PVA-AC） composite scaffolds were deve...The present work focused on developing an innovative composite material by reinforcing polymer matrix with highly porous activated charcoal. Polyvinyl alcohol-activated charcoal（PVA-AC） composite scaffolds were developed by varying the AC concentrations（0, 0.5, 1, 1.5, 2 and 2.5 wt%） in PVA matrix by freeze drying method. The developed scaffolds were characterized for their physicochemical, mechanical and in-vitro biological properties. In addition, the effect of AC on the attachment, proliferation and differentiation of osteoblast MG 63 cells was evaluated by scanning electron microscopy（SEM）, 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide（MTT） assay, alkaline phosphatase（ALP） activity assay and alizarin red stain-based（ARS） assay. All the PVA-AC composite scaffolds exhibited good bioactivity, hemocompatibility and protein adsorption properties. The scaffolds with high AC concentration（2.5 wt%） showed controlled drug release kinetics that are suitable for long term healing. The mechanical properties of all the PVA-AC composite scaffolds were improved when compared to the pure PVA scaffold. The high porosity, swelling degree and hydrophilicity of PVA-AC composite scaffolds facilitated cell attachment and proliferation. This is due to porous AC present in the sample that supported the osteoblast differentiation and formed mineralized nodules without the addition of any extra agents. From the above studies, it can be concluded that PVA-AC composite scaffolds are promising biomaterials for bone tissue engineering applications.展开更多
The iso fl avone calycosin-7-O-β-D-glucopyranoside(CG) is a principal constituent of Astragalus membranaceus(AR) and has been reported to inhibit osteoclast development in vitro and bone loss in vivo. The aim of this...The iso fl avone calycosin-7-O-β-D-glucopyranoside(CG) is a principal constituent of Astragalus membranaceus(AR) and has been reported to inhibit osteoclast development in vitro and bone loss in vivo. The aim of this study was to investigate the osteogenic effects of CG and its underlying mechanism in ST2 cells. The results show that exposure of cells to CG in osteogenic differentiation medium increases ALP activity, osteocalcin(Ocal) m RNA expression and the osteoblastic mineralization process. Mechanistically, CG treatment increased the expression of bone morphogenetic protein 2(BMP-2), p-Smad 1/5/8, β-catenin and Runx2, all of which are regulators of the BMP- or wingless-type MMTV integration site family(WNT)/β-catenin-signaling pathways. Moreover, the osteogenic effects of CG were inhibited by Noggin and DKK-1 which are classical inhibitors of the BMP and WNT/β-catenin-signaling pathways, respectively. Taken together, the results indicate that CG promotes the osteoblastic differentiation of ST2 cells through regulating the BMP/WNT signaling pathways. On this basis, CG may be a useful lead compound for improving the treatment of bone-decreasing diseases and enhancing bone regeneration.展开更多
Wnt signaling executes an indispensable performance in osteoblast differentiation,bone development,homeostasis,and remodeling.Wnt signals trigger the intracellular Wnt signaling cascade to initiate regulating the impl...Wnt signaling executes an indispensable performance in osteoblast differentiation,bone development,homeostasis,and remodeling.Wnt signals trigger the intracellular Wnt signaling cascade to initiate regulating the implication of b-catenin in the bone environment.Going through the novel discoveries done via high-throughput sequencing technologies on ge-netic mouse models,we highlighted the significant contribution of Wnt ligands,co-receptors,inhibitors,their related skeletal phenotypes in mouse models and the similar bone disorders clinically observed in human beings.Moreover,the crosstalk between Wnt signaling pathway and BMP,TGF-b,FGF,Hippo,Hedgehog,Notch and PDGF signaling pathways is thoroughly demonstrated to be the underlying gene regulatory network that orchestrates osteoblast dif-ferentiation and bone development.We also introspected the significance of Wnt signaling transduction in the reorganization of cellular metabolism by stimulating glycolysis,glutamine catabolism,and fatty acid oxidation in osteoblast-lineage cells that display an important reg-ulatory arbor in the cellular bioenergetics of the bone.Throughout this evaluation,most to date therapeutical approaches towards osteoporosis and other bone maladies found in human beings,are formulated with an aspiration to holistically revamp the present clinical applica-tions involving various monoclonal antibodies therapies that lack specificity,efficacy,and safety into more requisite advanced therapeutics that satisfy these three requirements for further clinical considerations.Conclusively,our review provides comprehensive scientific findings related to the fundamental significance of Wnt signaling cascades in skeletal system and the underlying gene regulatory network with other signaling pathways enlightening re-searchers with the possibility to further integrate the identified target molecules into thera-peutic strategies for skeletal disorders treatment in the clinic.展开更多
PIP5k1βis crucial to the generation of phosphotidylinosotol(4,5)P2.PIP5k1βparticipates in numerous cellular activities,such as B cell and platelet activation,cell phagocytosis and endocytosis,cell apoptosis,and cyto...PIP5k1βis crucial to the generation of phosphotidylinosotol(4,5)P2.PIP5k1βparticipates in numerous cellular activities,such as B cell and platelet activation,cell phagocytosis and endocytosis,cell apoptosis,and cytoskeletal organization.In the present work,we aimed to examine the function of PIP5k1βin osteoclastogenesis and osteogenesis to provide promising strategies for osteoporosis prevention and treatment.We discovered that PIP5k1β deletion in mice resulted in obvious bone loss and that PIP5k1β was highly expressed during both osteoclast and osteoblast differentiation.Deletion of the gene was found to enhance the proliferation and migration of bone marrow-derived macrophage-like cells to promote osteoclast differentiation.PIP5k1β-/-osteoclasts exhibited normal cytoskeleton architecture but stronger resorption activity.PIP5kip deficiency also promoted activation of mitogen-activated kinase and Akt signaling,enhanced TRAF6 and c-Fos expression,facilitated the expression and nuclear translocation of NFATC1,and upregulated Grb2 expression,thereby accelerating osteoclast differentiation and function.Finally,PIP5k1β enhanced osteoblast differentiation by upregulating master gene expression through triggering smad1/5/8 signaling.Therefore,PIP5k1βmodulates bone homeostasis and remodeling.展开更多
基金supported by the National Natural Science Foundation of China(32470399)Beijing Natural Science Foundation(5212014)Key Research and Development Program in the Ningxia Hui Autonomous Region,China(2020BBF02027).
文摘Chinese dwarf cherry(Cerasus humilis)is a fruit unique to China,which is considered to have osteoprotective effects.However,no systematic experimental characterization was available.In this study,the osteoprotective activity and mechanism of Chinese dwarf cherry polyphenol extract(OPE)was studied.In vitro,OPE stimulated the alkaline phosphatase activity in the early differentiation stage,increased the osteocalcin level in the middle differentiation stage,and induced the formation of more bonemineralized nodules in the late osteogenic stage.In vivo,OPE improved cancellous bone structure and maximum load of the femur in ovariectomized(OVX)rats.The balance between bone formation and resorption was regulated.Oxidative stress levels in the peripheral blood,liver and femur were reduced.OPE alleviated the disturbance in energy metabolism,muscle development,and muscle regulation-related signaling pathways caused by OVX and activated the calcium/adenosine monophosphate-activated protein kinase signaling pathway.Therefore,OPE is a potential dietary supplement for the prevention and treatment of osteoporosis.
基金This study was supported by the National Natural Science Foundation of China(No.81800343).
文摘Amyloid beta(AB)peptide 40 enhances the activation of receptor for advanced glycation end products(RAGE)in immune-inflammatory diseases.RAGE exhibits several ffects in the setting of numerous cardiovascular events.We bypothesized that the Aβ40/RAGE pathway is involved in the osteoblastic differentiation of the valvular interstitial cell(VIC)phenotype,and RAGE knockout intervention could reduce the calcification of aortic valve interstitial cells(AVICs)by inhibiting the extracellular-regulated kinase1/2(ERK 1/2)/nuclear factor kappa-B(NF-kB)signaling pathway.To test this hypothesis,the activation of AB40/RAGE pathway in human calcific AVs was evaluated with immunohistochemical staining.Cultured calcific VIC models were used in vitro.The VICs were stimulated using Aβ40,with or without RAGE small interfering ribonucleic acid(siRNA),and ERK1/2 and NF-κB inhibitors for analysis.Our data revealed that AB40 induced the ERK 1/2/NF-κB signaling pathway and osteoblastic differentiation of AVICs via the RAGE pathway in vitro.
文摘Biointerface design can greatly influence cell behavior. Therefore, in this study we examined the effects of three surface characteristics, roughness, chemistry, and wettability, on osteoblastic cell differentiation. We examined osteoblastic differentiation on titanium (Ti) samples with four levels of roughness (average roughness: 148.6 ± 23.1, 42 ± 6.2, 14.3 ± 5.5, 7.2 ± 1.6 nm) with or without a nanolayer coating of polydopamine (PDA). In vitro osteogenic differentiation was evaluated by quantifying alkaline phosphatase (AP) activity of human fetal preosteoblastic (hFOB 1.19) cells. The change in surface chemistry of Ti samples as a result of PDA coating was assessed by XPS analysis and water contact angle measurement. Results demonstrated that PDA treated samples were more hydrophilic, compared to untreated samples, and this was substrate roughness independent. Moreover, with the exception of the substrate with an oriented texture of surface nanotopography (RTi-4), the presence of a PDA nanolayer increased AP activity independent of substrate roughness. Our results suggest that surface chemistry and wettability, induced by a PDA nanolayer coating, had a greater effect on osteoblastic differentiation than did surface roughness.
基金supported by National Natural Science Foundation of China(grant numbers 82072523 to Zhiyong Hou)Postdoctoral program of Clinical medicine of Hebei Medical University(grant numbers PD2023012 to Sujuan Xu)+2 种基金Excellent postdoctoral research funding project of Hebei Province(grant numbers B2023005011 to Sujuan Xu)The 16th special grant of China Postdoctoral Science Foundation(grant numbers 2023T160182 to Sujuan Xu)Natural Science Foundation of Hebei Province,China(grant numbers H2023206230 to Yingchao Yin,H2024206186 to Sujuan Xu).
文摘The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis.Nuclear receptors(NRs)are now understood to be crucial in bone physiology and pathology.However,the function of the Farnesoid X receptor(FXR),a member of the NR family,in regulating bone homeostasis remains incompletely understood.In this study,in vitro and in vivo models revealed delayed bone development and an osteoporosis phenotype in mice lacking FXR in bone marrow mesenchymal stem cells(BMSCs)and osteoblasts due to impaired osteoblast differentiation.Mechanistically,FXR could stabilize RUNX2 by inhibiting Thoc6-mediated ubiquitination,thereby promoting osteogenic activity in BMSCs.Moreover,activated FXR could directly bind to the Thoc6 promoter,suppressing its expression.The interaction between RUNX2 and Thoc6 was mediated by the Runt domain of RUNX2 and the WD repeat of Thoc6.Additionally,Obeticholic acid(OCA),an orally available FXR agonist,could ameliorate bone loss in an ovariectomy(OVX)-induced osteoporotic mouse model.Taken together,our findings suggest that FXR plays pivotal roles in osteoblast differentiation by regulating RUNX2 stability and that targeting FXR may be a promising therapeutic approach for osteoporosis.
基金supported by grants from National Natural Science Foundation of China(82272444,81972031,81972033)China Postdoctoral Science Foundation(2022M722382)Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-032A)。
文摘Neural EGFL-like 2(NELL2)is a secreted protein known for its regulatory functions in the nervous and reproductive systems,yet its role in bone biology remains unexplored.In this study,we observed that NELL2 was diminished in the bone of aged and ovariectomized(OVX)mice,as well as in the serum of osteopenia and osteoporosis patients.In vitro loss-of-function and gain-offunction studies revealed that NELL2 facilitated osteoblast differentiation and impeded adipocyte differentiation from stromal progenitor cells.In vivo studies further demonstrated that the deletion of NELL2 in preosteoblasts resulted in decreased cancellous bone mass in mice.Mechanistically,NELL2 interacted with the FNI-type domain located at the C-terminus of Fibronectin 1(Fn1).Moreover,we found that NELL2 activated the focal adhesion kinase(FAK)/AKT signaling pathway through Fn1/integrinβ1(ITGB1),leading to the promotion of osteogenesis and the inhibition of adipogenesis.Notably,administration of NELL2-AAV was found to ameliorate bone loss in OVX mice.These findings underscore the significant role of NELL2 in osteoblast differentiation and bone homeostasis,suggesting its potential as a therapeutic target for managing osteoporosis.
文摘Carcinosarcomas are rare,malignant,biphasic tumors simultaneously comprising carcinoma and sarcoma in a single tumor.We present an extremely rare case of gastric carcinosarcoma with an osteoblastic component that drastically changed its shape within 2 mo.A 59-year-old male patient presented to the emergency outpatient unit with a complaint of black stool.Gastrointestinal endoscopy showed an ulcerated mass in the cardia of the lesser curvature of the stomach.Biopsy specimens revealed only adenocarcinoma.Two months later,the ulcerated lesion drastically changed its shape into an exophytic tumor.Total gastrectomy was performed.In the resected specimen,the gastric tumor contained both adenocarcinoma and sarcoma components with lace-like osteoid.The patient died 7 mo after the operation,and an autopsy was performed.In the autopsy,widespread metastases were present in the liver,lung,lymph nodes and peritoneum.In this report,we describe a case of gastric carcinosarcoma and presume its tumorigenesis based on the autopsy findings.
文摘In the recent two decades, it has been well elucidated that receptor activator of nuclear factor-κB ligand （RANKL; also known as TNFSF11） binding to its receptor RANK （also known as TNFRSF11A） drives osteoclast development as the crucial signaling pathway.;However, accumulating evidence also implies that
文摘Age-related osteoporosis is associated with the reduced capacity of bone marrow mesenchymal stem cells （BMSCs） to differentiate into osteoblasts instead of adipocytes. However, the molecular mechanisms that decide the fate of BMSCs remain unclear. In our study, microRNA-23a, and microRNA-23b （miR-23a/b） were found to be markedly downregulated in BMSCs of aged mice and humans. The overexpression of miR-23a/b in BMSCs promoted osteogenic differentiation, whereas the inhibition of miR-23a/b increased adipogenic differentiation. Transmembrane protein 64 （Tmem64）, which has expression levels inversely related to those of miR-23a/b in aged and young mice, was identified as a major target of miR-23a/b during BMSC differentiation. In conclusion, our study suggests that miR-23a/b has a critical role in the regulation of mesenchymal lineage differentiation through the suppression of Tmem64.
基金Project supported by CSIR,New Delhi Provided through the CSIR-network Project-Advanced Drug Delivery System(ADD-CSC0302)
文摘Adipose derived stem cells represent a readily available source of adult stem cells for various biomedical applications. In this study, the proliferation and osteogenic differentiation potential of lanthanum nitrate（La3＋） on human adipose derived mesenchymal stem cells（hADSCs） were investigated for the first time and compared with that of dexamethasone（Dex）. Our results provided evidence that La3＋ at 50 μmol/L concentration promoted proliferation of hADSCs upto 2.4 fold when treated for 21 d in DMEM medium. Treatment of hADSCs with La3＋ containing osteogenic induction medium（α-MEM with ascorbic acid and β-glycerophosphate） for 7 d resulted in higher calcium deposition than that in the presence of Dex（0.1 μmol/L） as shown by Alizarin red S and von Kossa staining. Scanning electron micrographs also showed more extracellular matrix mineralization in the presence of La3＋. After 7 d of treatment with La3＋（10 μmol/L） the expression of RunX2, osteopontin（OP） and osteocalcin（OC） increased 3.4, 5.5 and 2.7 fold respectively. Our results provided evidence that in the presence of La3＋ osteogenic differentiation occurred earlier than that in the presence of Dex.
基金supported by the Van Andel Research Instituteby a grant to BOW from the NIH/NIAMS (AR053293)
文摘99mTc-Methylene diphosphonate （99mTc-MDP） is widely used in clinical settings to detect bone abnormalities. However, the mechanism of 99mTc-MDP uptake in bone is not well elucidated. In this study, we utilized a mouse tibia injury model, single-photon emission computed tomography （gamma scintigraphy or SPECT）, ex vivo micro-computed tomography, and histology to monitor 99mTc-MDP uptake in injury sites during skeletal healing. In an ex vivo culture system, calvarial cells were differentiated into osteoblasts with osteogenic medium, pulsed with 99mTc-MDP at different time points, and quantitated for 99mTc-MDP uptake with a gamma counter. We demonstrated that 99mTc-MDP uptake in the injury sites corresponded to osteoblast generation in those sites throughout the healing process. The 99mTc-MDP uptake within the injury sites peaked on day 7 post-injury, while the injury sites were occupied by mature osteoblasts also starting from day 7. ~mTc-MDP uptake started to decrease 14 days post-surgery, when we observed the highest level of bony tissue in the injury sites. We also found that 99mTc-MDP uptake was associated with osteoblast maturation and mineralization in vitro. This study provides direct and biological evidence for 99mTc-MDP uptake in osteoblasts during bone healing in vivo and in vitro.
基金supported by NIH grants R01 DK065789 and R01 AR060456 to FL
文摘Indian hedgehog （Ihh） is an essential signal that regulates endochondral bone development. We have previously shown that Wnt7b promotes osteoblast differentiation during mouse embryogenesis, and that its expression in the perichondrium is dependent on Ihh signaling. To test the hypothesis that Wnt7b may mediate some aspects of Ihh function during endochondral bone development, we activated Wnt7b expression from the R26-Wnt7b allele with Col2-Cre in the Ihh-/- mouse. Artificial expression of Wnt7b rescued vascularization of the hypertrophic cartilage in the Ihh-/- mouse, but failed to restore orthotopic osteoblast differentiation in the perichondrium. Similarly, Wnt7b did not recover Ihh-dependent perichondral bone formation in the Ihh-/-; Gli3-/- embryo. Interestingly, Wnt7b induced bone formation at the diaphyseal region of long bones in the absence of Ihh, possibly due to increased vascularization in the area. Thus, Ihh-dependent expression of Wnt7b in the perichondrium may contribute to vascularization of the hypertrophic cartilage during endochondral bone development.
基金supported by the National Basic Research Program of China (973 Program, No. 2012CB619100)key program of the National Natural Science Foundation of China (No. 31430030the Natural Science Foundation of Guangdong Province (Nos. 2014A030310466 and 2013B060300007)
文摘Titanium （Ti） nanorods fabricated using selective corrosion of Ti substrate by anodic technology show better biocompatibility with pre-osteoblast cells. The current study investigated the response of the murine pre-osteoblast cell MCST3-E1 on Ti nanorod topography and untreated Ti surfaces by means of examination of the morphology and osteogenic differentiation responsible for the pre-osteoblast reaction. The morphology of MCST3-E1 cells was observed using scanning electron microscopy, and alkaline phosphatase （ALP） activity was measured using a colorimetric assay after incubation for 7, 14, and 21 days. The expression of three osteogenic differentiation markers including ALP, osteocalcin （OCN）, and collagen type 1A1 （COL1A1） and two transcription factors including runt related transcription factor 2 （Runx2） and osterix （Osx） at different time points was detected using real-time polymerase chain reaction analysis in both groups. Osx was used to confirm the protein level. The results showed that Ti nanorod surfaces provided prolonged higher levels of ALP activity compared with unmodified Ti surface on the 14th and 21st days. Gene expression analysis of ALP, OCN, and COL1A1 showed significant upregulation with modified nanorod topography after incubation for 14 and 21 days. Osteogenic transcription factors of Runx2 and Osx exhibited changes consistent with the osteogenic differentiation markers, and this may contribute to the persistently active differentiation of MC3T3-E1 cells in the Ti nanorod group. These results demonstrated that the current nanostructured surface may be considered bioadaptive topography to control cellular behaviors and osteoblast differentiation. The in vivo performance and applicability are further required to investigate osseointegration between implant and host bone in the early stages for prevention of aseptic implant loosening.
基金supported by the Natural Science Foundation Grants(No.81671826,No.81271702 and No.31600765)Sichuan Province Miaozi Project(2016RZ0032)Sichuan University Start-up Funding(2015SCU11041).
文摘While both induction culture media and matrix have been reported to regulate the stem cell fate,little is known about which factor plays a more decisive role in directing the MSC differentiation lineage as well as the underlying mechanisms.To this aim,we seeded MSCs on HA-collagen and HA-synthetic hydrogel matrixes,which had demonstrated highly different potentials toward osteoblastic and chondrocytic differentiation lineages,respectively,and cultured them with osteogenic,chondrogenic and normal culture media,respectively.A systematic comparison has been carried out on the effects of induction media and matrix on MSC adhesion,cytoskeleton organization,proliferation,and in particular differentiation into the osteoblastic and chondrocytic lineages.The results demonstrated that the matrix selection had a much more profound effect on directing the differentiation lineage than the induction media did.The strong modulation effect on the transcription activities might be the critical factor contributing to the above observations in our study,where canonical Wnt-b-Catenin signal pathway was directly involved in the matrix-driven osteoblastic differentiation.Such findings not only provide a critical insight on natural cellular events leading to the osteoblastic and chondrocytic differentiations,but also have important implications in biomaterial design for tissue engineering applications.
基金Korea Environment Industry&Technology Institute through Project to Make Multi-ministerial National Biological Research Resources more Advanced funded by Korea Ministry of Environment(No.:1485018221)Basic Science Research Program to Research Institute for Basic Sciences of Jeju National University through the National Research Foundation of Korea funded by the Ministry of Education(2019R1A6A1A10072987).
文摘Objective:To investigate the effect of an aqueous extract of Protaetia brevitarsis(AEPB)on osteogenesis using preosteoblast MC3T3-E1 cells and zebrafish larvae.Methods:Flow cytometric analysis was used to measure the cytotoxicy.Alkaline phosphatase activity was detetmined using p-nitrophenyl phosphate as a substrate.Calcium deposition was detected using alizarin red staining along with osteogenic marker expression in preosteoblast MC3T3E1 cells.In addition,vertebral formation in zebrafish larvae was detected using calcein staining and osteogenic gene expression.Results:AEPB highly promoted the expression of osteogenic markers including runt-related transcription factor 2,osterix,and alkaline phosphatase,along with elevated levels of mineralization in MC3T3-E1 cells.Moreover,AEPB accelerated vertebral formation in zebrafish larvae accompanied by upregulated expression of osteogenic genes.FH535,an inhibitor of Wnt/β-catenin,suppressed AEPB-induced osteogenic gene expression and vertebral formation,indicating that AEPB stimulates osteogenesis by activating the Wnt/β-catenin signaling pathway.Conclusions:AEPB stimulates osteoblast differentiation and bone formation by activatingβ-catenin.Therefore,AEPB is a promising material that induces osteogenesis,and is useful for the treatment of bone resorption diseases.
基金the National Natural Science Foundation of China(Nos.U1601220,82072450,and 81672118)Chongqing Science and Technology Commission-Basic Science and Frontier Technology Key Project(No.cstc2015jcyjBX0119)Chongqing Medical University Intelligent Medicine Research Project(No.ZHYX202115).
文摘Since 3D printed hard materials could match the shape of bone,cell survival and fate determination towards osteoblasts in such materials have become a popular research target.In this study,a scaffold of hardmaterial for 3D fabrication was designed to regulate developmental signal(Notch)transduction guiding osteoblast differentiation.We established a polycaprolactone(PCL)and cell-integrated 3D printing system(PCI3D)to reciprocally print the beams of PCL and cell-laden hydrogel for a module.This PCI3D module holds good cell viability of over 87%,whereas cells show about sixfold proliferation in a 7-day culture.The osteocytic MLO-Y4 was engineered to overexpress Notch ligand Dll4,making up 25%after mixing with 75%stromal cells in the PCI3D module.Osteocytic Dll4,unlike other delta-like family members such as Dll1 or Dll3,promotes osteoblast differentiation and themineralization of primary mouse and a cell line of bone marrow stromal cells when cultured in a PCI3D module for up to 28 days.Mechanistically,osteocytic Dll4 could not promote osteogenic differentiation of the primary bone marrow stromal cells(BMSCs)after conditional deletion of the Notch transcription factor RBPjκby Cre recombinase.These data indicate that osteocytic Dll4 activates RBPjκ-dependent canonical Notch signaling in BMSCs for their oriented differentiation towards osteoblasts.Additionally,osteocytic Dll4 holds a great potential for angiogenesis in human umbilical vein endothelial cells within modules.Our study reveals that osteocytic Dll4 could be the osteogenic niche determining cell fate towards osteoblasts.This will open a new avenue to overcome the current limitation of poor cell viability and low bioactivity of traditional orthopedic implants.
基金the Department of Biotechnology and Medical Engineering, The National Institute of Technology
文摘The present work focused on developing an innovative composite material by reinforcing polymer matrix with highly porous activated charcoal. Polyvinyl alcohol-activated charcoal（PVA-AC） composite scaffolds were developed by varying the AC concentrations（0, 0.5, 1, 1.5, 2 and 2.5 wt%） in PVA matrix by freeze drying method. The developed scaffolds were characterized for their physicochemical, mechanical and in-vitro biological properties. In addition, the effect of AC on the attachment, proliferation and differentiation of osteoblast MG 63 cells was evaluated by scanning electron microscopy（SEM）, 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide（MTT） assay, alkaline phosphatase（ALP） activity assay and alizarin red stain-based（ARS） assay. All the PVA-AC composite scaffolds exhibited good bioactivity, hemocompatibility and protein adsorption properties. The scaffolds with high AC concentration（2.5 wt%） showed controlled drug release kinetics that are suitable for long term healing. The mechanical properties of all the PVA-AC composite scaffolds were improved when compared to the pure PVA scaffold. The high porosity, swelling degree and hydrophilicity of PVA-AC composite scaffolds facilitated cell attachment and proliferation. This is due to porous AC present in the sample that supported the osteoblast differentiation and formed mineralized nodules without the addition of any extra agents. From the above studies, it can be concluded that PVA-AC composite scaffolds are promising biomaterials for bone tissue engineering applications.
基金supported by the National Natural Science Foundation of China, China (No. 31400304)the Natural Science Foundation of Hubei Province, China (No. 2012FFB00303)+1 种基金the Youth & Middle-aged Talent Project of Hubei Province (No. Q20111005)the Science and Technology Program of Shandong Province (No. J12LL07)
文摘The iso fl avone calycosin-7-O-β-D-glucopyranoside(CG) is a principal constituent of Astragalus membranaceus(AR) and has been reported to inhibit osteoclast development in vitro and bone loss in vivo. The aim of this study was to investigate the osteogenic effects of CG and its underlying mechanism in ST2 cells. The results show that exposure of cells to CG in osteogenic differentiation medium increases ALP activity, osteocalcin(Ocal) m RNA expression and the osteoblastic mineralization process. Mechanistically, CG treatment increased the expression of bone morphogenetic protein 2(BMP-2), p-Smad 1/5/8, β-catenin and Runx2, all of which are regulators of the BMP- or wingless-type MMTV integration site family(WNT)/β-catenin-signaling pathways. Moreover, the osteogenic effects of CG were inhibited by Noggin and DKK-1 which are classical inhibitors of the BMP and WNT/β-catenin-signaling pathways, respectively. Taken together, the results indicate that CG promotes the osteoblastic differentiation of ST2 cells through regulating the BMP/WNT signaling pathways. On this basis, CG may be a useful lead compound for improving the treatment of bone-decreasing diseases and enhancing bone regeneration.
基金supported by grants by Zhejiang Qianjiang Talent Program(No.21040040-E)the Department of Sci-Tech of Zhejiang Province(No.LGF19H140002)+4 种基金a startup grant from Zhejiang Sci-Tech University(No.18042290-Y,2021Q031)funds from National Natural Science Foundation of China(No.81900806,81400489)the basic Public Welfare Planning Project of Zhejiang Province(No.LGD20C040001)Jiaxing Science Technology Foundation(No.2020AY10001)Jiaxing Key Laboratory of Animal Model Generation and Precise Synthesis of New Drug Leads。
文摘Wnt signaling executes an indispensable performance in osteoblast differentiation,bone development,homeostasis,and remodeling.Wnt signals trigger the intracellular Wnt signaling cascade to initiate regulating the implication of b-catenin in the bone environment.Going through the novel discoveries done via high-throughput sequencing technologies on ge-netic mouse models,we highlighted the significant contribution of Wnt ligands,co-receptors,inhibitors,their related skeletal phenotypes in mouse models and the similar bone disorders clinically observed in human beings.Moreover,the crosstalk between Wnt signaling pathway and BMP,TGF-b,FGF,Hippo,Hedgehog,Notch and PDGF signaling pathways is thoroughly demonstrated to be the underlying gene regulatory network that orchestrates osteoblast dif-ferentiation and bone development.We also introspected the significance of Wnt signaling transduction in the reorganization of cellular metabolism by stimulating glycolysis,glutamine catabolism,and fatty acid oxidation in osteoblast-lineage cells that display an important reg-ulatory arbor in the cellular bioenergetics of the bone.Throughout this evaluation,most to date therapeutical approaches towards osteoporosis and other bone maladies found in human beings,are formulated with an aspiration to holistically revamp the present clinical applica-tions involving various monoclonal antibodies therapies that lack specificity,efficacy,and safety into more requisite advanced therapeutics that satisfy these three requirements for further clinical considerations.Conclusively,our review provides comprehensive scientific findings related to the fundamental significance of Wnt signaling cascades in skeletal system and the underlying gene regulatory network with other signaling pathways enlightening re-searchers with the possibility to further integrate the identified target molecules into thera-peutic strategies for skeletal disorders treatment in the clinic.
基金This work was supported by grants from the National Natural Science Foundation of China(81830078,81772347,and 81572123)Science and Technology Commission of Shanghai Municipality(19XD1434100 and 16430723500)+1 种基金Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(2016131A)Shanghai Jiao Tong University-The Chinese University of Hong Kong joint Research Collaboration Fund.
文摘PIP5k1βis crucial to the generation of phosphotidylinosotol(4,5)P2.PIP5k1βparticipates in numerous cellular activities,such as B cell and platelet activation,cell phagocytosis and endocytosis,cell apoptosis,and cytoskeletal organization.In the present work,we aimed to examine the function of PIP5k1βin osteoclastogenesis and osteogenesis to provide promising strategies for osteoporosis prevention and treatment.We discovered that PIP5k1β deletion in mice resulted in obvious bone loss and that PIP5k1β was highly expressed during both osteoclast and osteoblast differentiation.Deletion of the gene was found to enhance the proliferation and migration of bone marrow-derived macrophage-like cells to promote osteoclast differentiation.PIP5k1β-/-osteoclasts exhibited normal cytoskeleton architecture but stronger resorption activity.PIP5kip deficiency also promoted activation of mitogen-activated kinase and Akt signaling,enhanced TRAF6 and c-Fos expression,facilitated the expression and nuclear translocation of NFATC1,and upregulated Grb2 expression,thereby accelerating osteoclast differentiation and function.Finally,PIP5k1β enhanced osteoblast differentiation by upregulating master gene expression through triggering smad1/5/8 signaling.Therefore,PIP5k1βmodulates bone homeostasis and remodeling.
