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Spatially resolved osteoblast-traced transcriptomics uncovers TGF-βas a combination target with sclerostin in osteoporosis 认领 引用
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作者 Ahyoun Choi Ji Yeon Lee +14 位作者 Hyejin Yoon Xiangguo Che Minkyeong Choi Yongkuk Park Kyoungseob Shin Hyunho Lee Jimin Park Sung Hye Kong Jinhyun Kim Amos Chungwon Lee Chan Soo Shin Je-Yong Choi Jungwoo Lee Sunghoon Kwon Sang Wan Kim 《Bone Research》 SCIE CAS CSCD 2026年第2期640-652,共13页
Dynamic transitions of mature osteoblasts between active and quiescent states are essential for bone homeostasis and present a promising target for osteoanabolic therapy.However,these transitions remain poorly underst... Dynamic transitions of mature osteoblasts between active and quiescent states are essential for bone homeostasis and present a promising target for osteoanabolic therapy.However,these transitions remain poorly understood due to cellular heterogeneity and limited spatial context.Here,we employed spatially resolved osteoblast-traced transcriptomics,integrating an osteoblast-specific lineage tracing study and spatially resolved laser-activated cell sorting(SLACS),to profile osteoblast states on quiescent bone surfaces.This approach identified transforming growth factor-beta(TGF-β)signaling as a regulator of osteoblast activation.We further validated this role using single-cell RNA sequencing,in vitro functional assays,and in vivo.In a hindlimb unloading mouse model,dual inhibition of TGF-βand sclerostin enhanced bone mass and mitigated bone loss more effectively than sclerostin inhibition alone.These findings reveal a mechanistic role for TGF-βin regulating osteoblast dynamics and propose a dual-target therapeutic strategy that enhances the efficacy of anti-sclerostin treatment in osteoporosis. 展开更多
关键词 osteoanabolic therapyhoweverthese profile osteoblast states sclerostin spatially resolved osteoblast traced transcriptomics transforming growth factor beta bone homeostasis cellular heterogeneity osteoblast activation
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Linalool Promotes Osteoblast Differentiation via SELENBP1-Dependent Signaling in MC3T3-E1 and C3H10T1/2 Cells 认领 引用
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作者 Kyeong-Min Kim A-Rang Kim Won-Gu Jang 《BIOCELL》 SCIE 2026年第7期195-207,共13页
Background:Linalool is a monoterpene alcohol with known anti-inflammatory and antioxidant properties,but its role in osteoblast differentiation remains unclear.This study aimed to investigate the osteogenic potential ... Background:Linalool is a monoterpene alcohol with known anti-inflammatory and antioxidant properties,but its role in osteoblast differentiation remains unclear.This study aimed to investigate the osteogenic potential of linalool and to examine the role of selenium-binding protein 1(Selenbp1)in mediating its effects.Methods:Murine MC3T3-E1 and C3H10T1/2 cells were treated with linalool under osteogenic conditions.Osteoblast differentiation was assessed by alkaline phosphatase(ALP)activity,Alizarin Red S staining,and expression of runt-related transcription factor 2(Runx2)and distal-less homeobox 5(Dlx5).The involvement of Selenbp1 was examined using siRNA knockdown and plasmid overexpression.A zebrafish caudal fin regeneration model was used to evaluate in vivo relevance.Results:Linalool significantly enhanced osteoblast differentiation,as evidenced by increased ALP activity(approximately 3–4-fold vs.control,p<0.01)and matrix mineralization(approximately 2.5–4-fold increase,p<0.01).The osteogenic transcription factors Runx2 and Dlx5 were significantly upregulated following linalool treatment(p<0.01).Linalool also markedly induced Selenbp1 expression,showing an approximately 4–5-fold increase in MC3T3-E1 cells and an approximately 8–9-fold increase in C3H10T1/2 cells(p<0.01).Silencing Selenbp1 attenuated the linalool-induced upregulation of osteogenic markers,whereas its overexpression restored marker expression and enhanced cellular responsiveness to linalool.In vivo,linalool significantly increased zebrafish caudal fin regeneration by approximately 30–45%compared with the vehicle control(p<0.001).Conclusion:Linalool promotes SELENBP1-dependent osteoblast differentiation in vitro and enhances caudal fin regeneration in vivo,although the involvement of SELENBP1 in the latter was not examined. 展开更多
关键词 Linalool selenium-binding protein 1 preosteoblast mesenchymal stem cell osteoblast differentiation
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Exploring the dual effects of coffee water extract on osteoclastogenesis and osteoblastogenic mechanisms:in vitro and in vivo insights 认领 引用
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作者 Yue Miao Shuwen Lei +6 位作者 Chunyan Zhao Lei Zhao Qingfei Zou Qiuping Wang Chao Tan Chunxiu Peng Jiashun Gong 《Food Science and Human Wellness》 SCIE CAS CSCD 2026年第3期1227-1242,共16页
Epidemiological studies have reported varying associations between coffee consumption and bone mineral density.This study aims to systematically asses the pharmacological effects of prolonged coffee intake on osteobla... Epidemiological studies have reported varying associations between coffee consumption and bone mineral density.This study aims to systematically asses the pharmacological effects of prolonged coffee intake on osteoblasts,osteoclasts,and postmenopausal osteoporosis induced by ovariectomy.In vitro,experiments revealed that coffee water extract upregulated the expression of osteogenic-related proteins such as 12.5 μg/mL middle concentration group had a 1.33 fold increase in collagen type I α 1(COL1A1) expression,and a 1.83 fold increase in Osterix expression by inhibiting the phosphorylation of protein kinase B(AKT),inhibitor of κB protein-α(IκBα),P65,and extracellular signal-regulated kinase(ERK).Additionally,it inhibited receptor activator of nuclear factor kappa B ligand(RANKL)-mediated osteoclastogenesis in RAW264.7 cells though the AKT,MAPKs,and NF-κB pathways,concomitant with the inhibition of nuclear translocation of nuclear factor of activated T cells cytoplasmic 1.In vivo studies demonstrated that a medium-dose coffee sample inhibited osteoclastogenesis,stimulated osteogenesis,and ameliorated bone loss in ovariectomized mice.Molecular docking analysis validated the impact of caffeine,cholorogenic acids,and trigonelline on bone homeostasis.In summary,consumption of 4-5 cups of coffee per day in humans may attenuate ovariectomy(OVX)-associated pathological bone loss by disrupting osteoclast activity and promoting osteogenesis,while long-term consumption of high-dose coffee could disrupt bone homeostasis. 展开更多
关键词 Coffee water extract Osteoclast Osteoblasts Bone metabolism Osteoporosis Molecular docking
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Osteoblast-derived CAR3 synergizing with collagen and bone sialoprotein enhances bone formation 认领 引用
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作者 Xiaoxin Ma Qing He +7 位作者 Chen Ye Jinglun Zhang Xinyi Zhou Yuxuan Zhang Tian Gan Zhe Li Fangfang Song Yufeng Zhang 《International Journal of Oral Science》 SCIE CAS CSCD 2026年第3期374-385,共12页
Osteoblasts orchestrate the infiltration and crystallization of mineral precursors within collagen fibrils.Certain osteoblast-secreted mineralization-inducing proteins further stimulate bone formation.In this study,sc... Osteoblasts orchestrate the infiltration and crystallization of mineral precursors within collagen fibrils.Certain osteoblast-secreted mineralization-inducing proteins further stimulate bone formation.In this study,scRNA-seq analysis of murine skull and long bone revealed a striking expression pattern of carbonic anhydrase Ⅲ(Car3)in osteoblasts.We uncovered a pivotal role for CAR3 in osteoblast lineage cells,revealing its critical function in skeletal development and homeostasis.Conditional ablation of Car3 in Prx1-lineage cells resulted in osteopenia and markedly impaired osteoblast activity,underscoring its functional role.Mechanistically,the primary transcription factor RUNX2 directly regulated Car3 expression,mediating its spatiotemporal expression during development.Notably,CAR3 promoted collagen intrafibrillar mineralization by forming a ternary complex with COL1A1 and bone sialoprotein(BSP),thereby facilitating mineral deposition.Furthermore,CAR3-functionalized scaffolds significantly improved bone repair and regeneration by promoting both matrix mineralization and recruitment of Prx1-lineage cells.These findings establish CAR3 as a critical coordinator of osteoblast differentiation and collagen interfibrillar mineralization,positioning it as a central mediator for maintaining skeletal integrity and enabling regeneration. 展开更多
关键词 bone sialoprotein mineral precursors carbonic anhydrase bone formation collagen fibrilscertain osteoblasts collagen runx
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Echinacoside targets HSC70 to promote osteoblast differentiation via Wnt/β-catenin signaling activation and mitochondrial regulation 认领 引用
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作者 Dong Han Shihao Chen +4 位作者 Xiaojuan Wu Xiaoli Jiang Ping Li Weilong Xu Fei Li 《Chinese Journal of Natural Medicines》 SCIE CAS CSCD 2026年第6期734-744,共11页
Osteoporosis(OP)is characterized by impaired osteoblast activity and excessive bone resorption,yet effective anabolic therapies remain limited.Here,we identify heat shock cognate 71 kDa protein(HSC70)as a novel negati... Osteoporosis(OP)is characterized by impaired osteoblast activity and excessive bone resorption,yet effective anabolic therapies remain limited.Here,we identify heat shock cognate 71 kDa protein(HSC70)as a novel negative regulator of osteoblast differentiation and reveal echinacoside(ECH),a natural phenylethanoid glycoside from Cistanche deserticola,as its direct inhibitor.Functional studies demonstrated that inhibition or knockdown of Hsc70 promoted osteoblast differentiation and mineralization,while Hsc70 overexpression abrogated the effects of ECH.Mechanistically,ECH suppressed HSC70 activity to activate Wnt/β-catenin signaling,enhanceβ-catenin nuclear translocation,and improve mitochondrial dynamics,ATP production,and biogenesis,thereby providing metabolic support for osteogenesis.In vivo,ECH treatment and hsc70 knockout alleviated glucocorticoid-induced bone loss and restored mineralization in zebrafish models.Collectively,this work uncovers the HSC70–β-catenin/mitochondrial axis as a druggable pathway for skeletal homeostasis and positions ECH as a promising natural lead for developing bone-anabolic therapies against OP. 展开更多
关键词 Echinacoside HSC70 Osteoblast differentiation Mitochondria Osteoporosis
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PTH induced osteoblast Slit3 to decrease aberrant sensory innervation in degenerated vertebral endplates to relieve low back pain in mice 认领 引用
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作者 Weixin Zhang Arryn D.Otte +4 位作者 Zhuolun Wang Sisir Kumar Barik Mei Wan Xu Cao Janet L.Crane 《Bone Research》 SCIE CAS CSCD 2026年第1期152-165,共14页
During aging,the spine undergoes degenerative changes,particularly with vertebral endplate bone expansion and sclerosis,that are associated with nonspecific low back pain.We report that parathyroid hormone(PTH)treatme... During aging,the spine undergoes degenerative changes,particularly with vertebral endplate bone expansion and sclerosis,that are associated with nonspecific low back pain.We report that parathyroid hormone(PTH)treatment reduced vertebral endplate sclerosis and improved pain behaviors in three mouse models of spinal degeneration(aged,SM/J,and young lumbar spine instability mice).Aberrant innervation in the vertebral body and endplate during spinal degeneration was decreased with PTH treatment as quantified by PGP9.5+and CGRP+nerve fibers,as well as CGRP expression in dorsal root ganglia.The neuronal repulsion factor Slit3 significantly increased in response to PTH treatment mediated by transcriptional factor FoxA2.PTH type 1 receptor and Slit3 deletion in osteocalcin-expressing cells prevented PTH-reduction of endplate porosity and improvement in behavior tests.Altogether,PTH stimulated osteoblast production of Slit3,decreased aberrant sensory nerve innervation,and provided symptomatic relief of LBP associated with mouse spinal degeneration. 展开更多
关键词 mouse models vertebral endplate vertebral body osteoblasts spinal degeneration agedsm jand slit improved pain behaviors spinal degeneration
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Exposure to 6-PPD quinone suppresses the proliferation and differentiation of osteoblasts by Nr4a1-p38 MAPK signal axis 认领 引用
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作者 Peiwen Wang Lianghui Lu +4 位作者 Xiaochao Tan Chunqing Han Xiping Hu Huanliang Liu Yu Wu 《Journal of Environmental Sciences》 SCIE EI CAS CSCD 2026年第7期277-284,共8页
6-PPD quinone(6-PPDQ),a new environmental contaminant,has been frequently detected in different environmental matrices and widely identified as causing health hazard.However,most early studies have primarily reported ... 6-PPD quinone(6-PPDQ),a new environmental contaminant,has been frequently detected in different environmental matrices and widely identified as causing health hazard.However,most early studies have primarily reported 6-PPDQ-induced toxic effects on visceral organs but do not consider its skeletal toxicity as well as the associated molecular mechanism after 6-PPDQ exposure,which remains largely unknown.This study investigated the impacts of 6-PPDQ on skeleton in vitro and in vivo.Four-week repeated 8 mg/kg 6-PPDQ exposure inhibited the bone formation,possibly by affecting osteoblasts rather than osteoclasts in mice.Moreover,10μg/L 6-PPDQ exposure inhibited osteoblast proliferation and differentiation by inhibiting Nr4a1 and p38 MAPK pathway.Additionally,Nr4a1 functioned upstream of p38 MAPK signaling to control the 6-PPDQ-induced suppression on osteoblasts proliferation and differentiation.Briefly,10μg/L 6-PPDQ exposure suppressed the activation of Nr4a1-p38 MAPK signal axis to further suppress osteoblasts proliferation and differentiation.Consequently,the present work helps understand possible skeletal toxicity induced by 10μg/L 6-PPDQ exposure in mammals and provides novel intervention targets for the therapy of skeletal diseases caused by environmental toxicants in humans. 展开更多
关键词 Skeletal toxicity 6-PPDQ Osteoblasts Nr4a1 p38 MAPK
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Red ginseng-derived nanovesicles to modulate osteoblast and osteoclastogenesis for osteoporosis therapy 认领 引用
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作者 Dong-ha Kim Se Hwan Mun +11 位作者 Jae-Hee Kwon Bum-Joon Koo Hyun-Woo Kim Sang-Hun Choi Kwang-Won Seo Young Yang Yong Yook Lee Jin Sun Jung Do-Kyun Kim Moon-Chang Baek Jihoon Kim Young-Eun Cho 《Asian Journal of Pharmaceutical Sciences》 SCIE CAS CSCD 2026年第3期131-152,共22页
Osteoporosis is a skeletal disorder characterized by an imbalance between bone formation and resorption,which leads to progressive bone loss and increased fracture risk.While current treatments either inhibit bone res... Osteoporosis is a skeletal disorder characterized by an imbalance between bone formation and resorption,which leads to progressive bone loss and increased fracture risk.While current treatments either inhibit bone resorption or stimulate bone formation,their long-term use is associated with adverse effects,necessitating alternative therapeutic approaches.In this study,we explore the use of red ginseng-derived nanovesicles(RGNVs)as a biocompatible nanotherapeutic strategy for treating osteoporosis.The RGNVs were successfully isolated and characterized,revealing a lipid bilayer structure enriched in bioactive ginsenosides and functional proteins.In vitro,RGNVs enhanced osteoblast proliferation,differentiation,and mineralization while suppressing osteoclast differentiation and bone resorption by modulating the BMP-2/Smad and MAPK signaling pathways.In an ovariectomy-induced osteoporosis mouse model,oral administration of RGNVs significantly restored bone volume and mineral density,and biodistribution studies confirmed their preferential accumulation in the bone tissue.Systemic toxicity evaluation indicated no adverse effects,supporting the safety of RGNVs for therapeutic use.These findings suggest that RGNVs regulate bone remodeling through a dual mechanism,to stimulate bone formation and inhibit bone resorption,thereby offering a promising and well-tolerated approach for osteoporosis management. 展开更多
关键词 Red ginseng-derived nanovesicles(RGNVs) Osteoporosis Osteoblast differentiation Osteoclast inhibition Bone regeneration
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Modeling the chondrocyte-derived osteoblasts formation process reveals its molecular signature and regulation network 认领 引用
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作者 Raquel Ruiz-Hernández Laurie Gay +21 位作者 Verónica Moncho-Amor Pablo Martín Jhonatan A.Vergara-Arce Stefania Di Blasio Thomas Snoeks Unai Cossío Ander Matheu Maria M.Caffarel Daniela Gerovska Marcos J.Araúzo-Bravo Amaia Vilas Felipe Prosper Sergio Moya Daniel Alonso-Alconada Ana Alonso-Varona Gretel Nusspaumer Javier Lopez-Rios Karine Rizotti Robin Lovell-Badge Dominique Bonnet Ilaria Malanchi Ander Abarrategi 《Bone Research》 SCIE CAS CSCD 2026年第1期291-302,共12页
Endochondral ossification is a physiological process involving a sequential formation of cartilage and bone tissues.Classically,cartilage and bone formation have been considered independent processes at cellular level... Endochondral ossification is a physiological process involving a sequential formation of cartilage and bone tissues.Classically,cartilage and bone formation have been considered independent processes at cellular level.However,the recently described multiple cell differentiation dynamics suggest that some bone cells are indeed the progeny of cartilage cells,or chondrocyte-derived osteoblasts.We hypothesized that the cartilage-to-bone phenotype transition is triggered by specific molecular events.First,the process was assessed in mouse bone tissue,and then,it was mimicked using in vivo cell implantation and in vitro serial differentiation protocols.Data indicates that cartilage cells transition to bone cell phenotype during postnatal physiological bone formation.This process can be reproduced using cartilage precursor cells coupled to specific implantation procedures or differentiation protocols.Gene expression profiling reveals that NOTCH,BMP and MAPK signaling pathways are relevant at the phenotype-switch,while the transcription factors Mesp1,Alx1,Grhl3 and Hmx3 are the feasible driver genes for chondrocyte-derived osteoblasts formation.Altogether,this report shows that endochondral ossification can be modeled using primary cell cultures and data indicate that this process is regulated by specific molecular events,previously described at skeleton morphogenesis during embryo development,and from now on also linkable to postnatal bone development and regeneration processes. 展开更多
关键词 regulation network postnatal bone development chondrocyte derived osteoblasts multiple cell differentiation dynamics molecular signature bone tissuesclassicallycartilage bone cells endochondral ossification
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Effects and mechanism of conditional osteoblast PHB1 knockout on bone metabolism in mice 认领 引用
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作者 Jia-Hui Li Zheng Shan +5 位作者 Wen-Wei Xie Yan-Ling Deng Bing-Qing Wang Shi-Long Fan Qing-Yu Feng Zhi-Kun Zhou 《Biomedical Engineering Communications》 CAS 2026年第5期64-75,共12页
Background:Postmenopausal osteoporosis(PMOP)is a highly prevalent metabolic bone disorder with limited effective clinical therapies.To verify prohibitin 1(PHB1)as a potential therapeutic target for PMOP,we generated a... Background:Postmenopausal osteoporosis(PMOP)is a highly prevalent metabolic bone disorder with limited effective clinical therapies.To verify prohibitin 1(PHB1)as a potential therapeutic target for PMOP,we generated an osteoblast-specific PHB1 conditional knockout(CKO)mouse model.This strategy is based on our preliminary results that Huangqi Sanxian Decoction enhances osteogenesis by inhibiting PHB1 expression,indicating that PHB1 may serve as a critical negative regulator of bone formation.Methods:An osteoblast-specific PHB1 conditional knockout(CKO)mouse model was established for in vivo experiments.In vitro assays were conducted to evaluate the biological functions of PHB1 knockout on osteoblasts,including assessments of cell proliferation,differentiation,and survival.Molecular analyses were performed to detect the expression of osteogenic markers and the activity of the PI3K/Akt signaling pathway.Results:Compared to controls,CKO mice exhibited significantly increased bone mineral density(BMD),elevated bone formation marker(PINP),and reduced bone resorption marker(CTX-1)and osteoclast number.In vitro,PHB1 knockout enhanced osteoblast proliferation,differentiation(increased ALP activity and mineralization),and survival(elevated Bcl-2/Bax ratio,decreased caspase-3),while upregulating osteogenic markers(OPN,Runx2).Mechanistically,the PI3K/Akt pathway was activated,as indicated by an increased p-Akt/Akt ratio.Conclusion:These findings demonstrate that osteoblast-specific PHB1 deletion promotes bone formation and inhibits resorption via the PI3K/Akt pathway,offering a mechanistic foundation for PHB1-targeted therapies in PMOP. 展开更多
关键词 PHB1 gene Conditional knockout PI3K/Akt Osteoblast Bone metabolism
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Vitamin K-dependent carboxylation in osteoblasts regulates bone resorption through GAS6 in male mice 认领 引用
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作者 Monica Pata Diep Ngoc Thi Pham +5 位作者 Julie Lacombe BAshok Reddy Young Woong Kim Abeer Gamal Ali Ahmed Monzur Murshed Mathieu Ferron 《Bone Research》 SCIE CAS CSCD 2026年第3期879-891,共13页
Studies in humans suggest that vitamin K is involved in the regulation of bone remodeling,but the precise mechanism at play remains unknown.In cells,vitamin K functions as a co-factor for theγ-glutamyl carboxylase(GG... Studies in humans suggest that vitamin K is involved in the regulation of bone remodeling,but the precise mechanism at play remains unknown.In cells,vitamin K functions as a co-factor for theγ-glutamyl carboxylase(GGCX),an enzyme responsible for the conversion of glutamic acid residues(Glu)intoγ-carboxyglutamic acid(Gla)residues in secreted proteins.We aim here at determining the role ofγ-carboxylation in bone remodeling and at identifying the Gla protein(s)involved.We show that male mice lackingγ-carboxylation specifically in osteoblasts(Ggcxflox/flox;OCN-Cre)have increased bone mass at 6 months of age due to a reduced number of multinucleated bone resorbing osteoclasts.In co-culture experiments,Ggcx-deficient osteoblasts were less effective than control osteoblasts at supporting osteoclast formation.Among known Gla proteins,we identify GAS6 as an osteoblast-secretedγ-carboxylated factor which signals to differentiating osteoclasts.The GAS6 receptors MerTK and AXL are expressed in pre-osteoclasts and pharmacological inhibitors of AXL and MerTK block osteoclast generation in co-culture.Conversely,recombinantγ-carboxylated GAS6 dose-dependently increases the size of osteoclasts and the number of nuclei per osteoclast in culture.GAS6 marginally affected the induction of osteoclast-specific genes during osteoclast differentiation but significantly increased pre-osteoclast fusion.Finally,increasing bone marrow GAS6 level in transgenic male mice was sufficient to increase the number and size of osteoclasts and to decrease bone mass.This work identifies GAS6 as a novel osteoblast-derived vitamin K-dependent protein regulating osteoclast maturation. 展开更多
关键词 glutamic acid bone remodelingbut osteoblasts bone remodeling Gas bone resorption osteoclasts vitamin k
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Osteoblastic sclerostin loop3-LRP4 interaction required by sclerostin to inhibit bone formation 认领 引用
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作者 Luyao Wang Xiaohui Tao +23 位作者 Hewen Jiang Shijian Ding Ning Zhang Xin Yang Shenghang Wang Yihao Zhang Nanxi Li Haitian Li Zhanghao Li Xiaoxin Wen Meiheng Sun Chuanxin Zhong Heiwa So Jin Liu Yuanyuan Yu Hua Yue Xianghang Luo Péter Ferdinandy Tao Zhang Shu Zhang Zhenlin Zhang Aiping Lu Baoting Zhang Ge Zhang 《Bone Research》 SCIE CAS CSCD 2026年第3期949-962,共14页
Sclerostin negatively regulates bone formation.The marketed antibody against sclerostin loop2 promoted bone formation but may have caused severe cardiovascular events in clinical use.In our published studies,sclerosti... Sclerostin negatively regulates bone formation.The marketed antibody against sclerostin loop2 promoted bone formation but may have caused severe cardiovascular events in clinical use.In our published studies,sclerostin loop3 was found to be involved in inhibitory effects of sclerostin on bone formation,whereas cardiovascular protective effects of sclerostin in mice were independent of loop3.It is necessary to investigate how sclerostin loop3 participates in the inhibitory effects of sclerostin on bone formation to facilitate developing precise strategies that promote bone formation without increasing cardiovascular risk.In this study,sclerostin loop3 was identified to bind to LRP4,thereby facilitating binding of sclerostin to LRP6 in osteoblasts.Blockade of sclerostin loop3-LRP4 interaction by both Lrp4 mutation(Lrp4m)and blocking peptide(LRP4-Pep)diminished the antagonistic effect of sclerostin on Wnt/β-catenin signaling in osteoblasts in vitro.Consistently,Lrp4m promoted bone formation in Lrp4m mice in vivo.Mechanistically,osteoblast-conditional correction of Lrp4m to wild-type Lrp4 resulted in significantly lower bone formation than Lrp4m mice,indicating that the promotive effects of Lrp4m on bone formation acted in osteoblasts in vivo.Moreover,re-expression of sclerostin dramatically inhibited bone formation in sost−/−mice,whilst the inhibitory effects of sclerostin were significantly weaker in sost−/−.Lrp4m mice.Pharmacologically,LRP4-Pep diminished the inhibitory effects of sclerostin on bone formation in SOSTki mice.Taken together,osteoblastic sclerostin loop3-LRP4 interaction,as an anchor,was required by sclerostin to bind to LRP6,thereby inhibiting bone formation.Translationally,blockade of sclerostin loop3-LRP4 interaction in osteoblasts would provide precise therapeutic strategies to promote bone formation without increasing cardiovascular risk. 展开更多
关键词 Wnt catenin signaling osteoblastic interaction sclerostin loop bone formation LRP cardiovascular risk
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Promoting osteoblast-mediated bone formation:a more promising approach for natural products to treat osteoporosis 认领 引用
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作者 Peixuan Hu Meipeng Zhu +1 位作者 Feng Li Jian Liu 《Chinese Journal of Natural Medicines》 SCIE CAS CSCD 2026年第2期156-170,共15页
Osteoporosis is a systemic skeletal disorder characterized by reduced bone mass,compromised bone microstructure,and an increased risk of fractures,primarily due to excessive osteoclast-mediated bone resorption relativ... Osteoporosis is a systemic skeletal disorder characterized by reduced bone mass,compromised bone microstructure,and an increased risk of fractures,primarily due to excessive osteoclast-mediated bone resorption relative to osteoblast-mediated bone formation.While current anti-osteoporosis drugs,such as bisphosphonates and denosumab,predominantly focus on reducing bone resorption,osteoanabolic approaches are essential for restoring bone microarchitecture and ultimately reducing fracture risk.Traditional Chinese medicines(TCMs)and their active ingredients have long been used in China for osteoporosis prevention and treatment.This review provides a comprehensive evaluation of the effects and molecular mechanisms of 65 natural products across 24 categories on osteoblast-mediated bone formation.These compounds promote bone formation by regulating key transcription factors(RUNX2 and Osterix)and signaling pathways,including WNT/β-catenin,bone morphogenic protein(BMP),mitogen-activated protein kinase(MAPK),phosphoinositide 3-kinase/protein kinase B(PI3K/AKT),oxidative stress,autophagy,and epigenetic regulation.Notably,certain natural products[e.g.,icariin(ICA)]exert their effects through multiple targets and pathways.Many of these natural products have demonstrated significant therapeutic efficacy in animal models,such as ovariectomized(OVX)mice.Our findings suggest that natural products with kidney-tonifying,anti-inflammatory,and antioxidant properties,as well as those inhibiting adipocyte differentiation,may hold promise for osteoporosis treatment.Additionally,we highlight current research gaps and propose future directions,including high-throughput screening and validation in diverse animal models,development of novel bone-targeting delivery systems,and identification of natural compounds targeting osteocytes. 展开更多
关键词 Natural products Osteoblasts Bone formation Osteoporosis
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Lithospermic Acid Promotes Osteoblast Proliferation and Differentiation through the Wnt/β-Catenin Signaling Pathway 认领 引用
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作者 Jianfeng Wang Zhongqing Hu +5 位作者 Jiandong Guo Xin Jin Lei Cai Jian Li Jinxi Zhang Dongan He 《BIOCELL》 SCIE 2026年第2期128-147,共20页
Objectives Therapeutic strategies for enhancing bone regeneration and combating osteoporosis remain a significant unmet medical need.This study aims to elucidate Lithospermic acid(LA)’s regulatory effects on osteobla... Objectives Therapeutic strategies for enhancing bone regeneration and combating osteoporosis remain a significant unmet medical need.This study aims to elucidate Lithospermic acid(LA)’s regulatory effects on osteoblast proliferation and differentiation,investigating its viability as a bone-healing agent.Methods This study employed various cellular and molecular biology experiments to assess the effects of LA on the viability,proliferation,cell cycle,apoptosis,differentiation,mineralization,and migration of MC3T3-E1 osteoblasts.Immunofluorescence and Western blot analyses were conducted to detect the expression of proteins related to the Wnt/β-catenin signaling pathway,investigating the regulatory mechanisms by which LA promotes osteoblast proliferation and differentiation.Additionally,Wnt inhibitor dickkopf-1(DKK-1)andβ-catenin-silenced cell models were used to further validate the role of LA in modulating this signaling pathway.Results LA significantly promoted osteoblast proliferation without apparent cytotoxicity.Flow cytometry showed that LA regulated the cell cycle by reducing G0/G1 phase arrest and promoting G2/M phase progression.Western blot results indicated that LA upregulated the expression of proteins associated with cell proliferation and enhanced osteoblast differentiation and mineralization.Immunofluorescence and Western blot analyses further confirmed that LA markedly increased the expression of Wnt andβ-catenin,facilitatingβ-catenin nuclear translocation.Treatment with the DKK-1 inhibitor significantly diminished the proliferative and differentiation-promoting effects of LA,confirming the critical role of this pathway.β-catenin knockdown experiments further substantiated its central role in LA-mediated regulation.Conclusion This study confirms that LA promotes osteoblast proliferation,differentiation,mineralization,and migration by activating the Wnt/β-catenin signaling pathway. 展开更多
关键词 Lithospermic acid osteoblasts cell proliferation cell differentiation Wnt/β-catenin signaling pathway
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Nuclear farnesoid X receptor protects against bone loss by driving osteoblast differentiation through stabilizing RUNX2 认领 引用 被引量：8
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作者 Qi Dong Haoyuan Fu +14 位作者 Wenxiao Li Xinyu Ji Yingchao Yin Yiran Zhang Yanbo Zhu Guoqiang Li Huiyang Jia Heng Zhang Haofei Wang Jinglue Hu Ganggang Wang Zhihao Wu Yingze Zhang Sujuan Xu Zhiyong Hou 《Bone Research》 SCIE CAS CSCD 2025年第2期401-416,共16页
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
关键词 Farnesoid X receptor osteoporosis phenotype vitro vivo models farnesoid x receptor fxr bone homeostasis nuclear receptor osteoblast differentiation bone marrow mesenchymal stem cell
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Salidroside inhibits osteoclast differentiation based on osteoblast-osteoclast interaction via HIF-1αpathway 认领 引用 被引量：2
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作者 Yutong Jin Yao Wang +7 位作者 Chuan Wang Lingling Zhang Dandan Gao Haizhao Liu Qingwen Cao Chenchen Tian Yuhong Bian Yue Wang 《Chinese Journal of Natural Medicines》 SCIE CAS CSCD 2025年第5期572-584,共13页
This study investigated the regulatory potential of salidroside(SAL),a primary active compound in Rhodiola rosea L.,on osteoclast differentiation by modulating the hypoxia-inducible factor 1-alpha(HIF-1α)pathway in o... This study investigated the regulatory potential of salidroside(SAL),a primary active compound in Rhodiola rosea L.,on osteoclast differentiation by modulating the hypoxia-inducible factor 1-alpha(HIF-1α)pathway in osteoblasts.Luciferase reporter assay and chromatin immunoprecipitation(Ch IP)assay were employed to validate whether the receptor activator of nuclear factor-κB ligand(RANKL)is the downstream target gene of HIF-1αin osteoblasts.The study also utilized lipopolysaccharide(LPS)-induced mouse osteolysis to examine the impact of SAL on osteolysis in vivo.Furthermore,conditioned medium(CM)from SAL-pretreated osteoblasts was used to investigate the paracrine effects on osteoclastogenesis through the HIF-1αpathway.Hypoxic condition-induced overexpression of HIF-1αupregulated RANKL levels by binding to the RANKL promoter and enhancing transcription in osteoblastic cells.In vivo,SAL significantly alleviated bone tissue hypoxia and decreased the expression of HIF-1αby downregulating the expression of RANKL,vascular endothelial growth factor(VEGF),interleukin 6(IL-6),and angiopoietin-like 4(ANGPTL4).In the paracrine experiment,conditioned media from SAL-pretreated osteoblasts inhibited differentiation through the HIF-1α/RANKL,VEGF,IL-6,and ANGPTL4 pathways.RANKL emerges as the downstream target gene regulated by HIF-1αin osteoblasts.SAL significantly alleviates bone tissue hypoxia and bone loss in LPS-induced osteolysis through the HIF-1α/RANKL,VEGF,IL-6,and ANGPTL4 pathways.SAL inhibits osteoclast differentiation by regulating osteoblast paracrine secretion. 展开更多
关键词 Salidroside Hypoxia-inducible factor-1α Osteoblast Osteoclast Osteoclastogenesis
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NELL2,a novel osteoinductive factor,regulates osteoblast differentiation and bone homeostasis through fibronectin 1/integrin-mediated FAK/AKT signaling 认领 引用 被引量：2
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作者 Hairui Yuan Xinyu Wang +8 位作者 Shuanglin Du Mengyue Li Endong Zhu Jie Zhou Yuan Dong Shuang Wang Liying Shan Qian Liu Baoli Wang 《Bone Research》 SCIE CAS CSCD 2025年第4期895-909,共15页
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
关键词 adipocyte differentiation osteoblast differentiation fak akt signaling fibronectin bone biology secreted protein stromal progenitor cells bone homeostasis
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Chinese dwarf cherry[Cerasus humilis(Bge.)Sok.]polyphenol extract promotes osteoblastic differentiation in MC3T3-E1 cells and reduce ovariectomy-induced bone loss in rats via the calcium/AMPK signaling pathway 认领 引用
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作者 Yushi Zhang Qingyu Cui +4 位作者 Lixin Wang Xiaoxue Wang Shupeng Liu Rong Zeng Weidong Li 《Food Science and Human Wellness》 SCIE CAS CSCD 2025年第7期2846-2859,共14页
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
关键词 Osteoporosis Postmenopausal osteoporosis Osteoblast differentiation Osteoblast mineralization Oxidative stress Biomechanics of bone Transcriptome
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Membrane-initiated estrogen receptor-α signaling in osteoblasts is crucial for normal regulation of the cortical bone in female mice 认领 引用
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作者 Yiwen Jiang Karin Horkeby +11 位作者 Petra Henning Jianyao Wu Karin HNilsson Lina Lawenius Sofia Movérare-Skrtic Priti Gupta Cecilia Engdahl Antti Koskela Juha Tuukkanen Lei Li Claes Ohlsson Marie KLagerquist 《Bone Research》 SCIE CAS CSCD 2025年第5期1201-1210,共10页
Membrane-initiated estrogen receptorα(mERα)signaling has been shown to affect bone mass in murine models.However,it remains unknown which cell types mediate the mERα-dependent effects on bone.In this study,we gener... Membrane-initiated estrogen receptorα(mERα)signaling has been shown to affect bone mass in murine models.However,it remains unknown which cell types mediate the mERα-dependent effects on bone.In this study,we generated a novel mouse model with a conditional C451A mutation in Esr1,which enables selective knockout of the palmitoylation site essential for the membrane localization of ERα(C451Af/f).First,we used Runx2-Cre mice to generate Runx2-C451Af/fmice with conditional inactivation of mERαsignaling in Runx2-expressing osteoblast lineage cells.No significant changes were observed in body weight,weights of estrogen-responsive organs,or serum concentrations of estradiol between female Runx2-C451Af/fand homozygous C451Af/flittermate controls.High-resolution microcomputed tomography analysis showed a consistent decrease in cortical bone mass in the tibia,femur,and vertebra L5 of Runx2-C451Af/fmice and three-point bending analysis of humerus revealed an impaired mechanical bone strength in Runx2-C451Af/ffemale mice compared to controls.Additionally,primary osteoblast cultures from mice lacking mERαsignaling showed impaired differentiation compared to controls. 展开更多
关键词 female mice mouse model conditional inactivation mer signaling osteoblasts membrane initiated estrogen receptor alpha cortical bone palmitoylation selective knockout palmitoylation site
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The art of building bone: emerging role of chondrocyte-to-osteoblast transdifferentiation in endochondral ossification 认领 引用 被引量：17
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作者 Patrick Aghajanian Subburaman Mohan 《Bone Research》 SCIE CAS CSCD 2018年第3期217-225,共9页
There is a worldwide epidemic of skeletal diseases causing not only a public health issue but also accounting for a sizable portion of healthcare expenditures. The vertebrate skeleton is known to be formed by mesenchy... There is a worldwide epidemic of skeletal diseases causing not only a public health issue but also accounting for a sizable portion of healthcare expenditures. The vertebrate skeleton is known to be formed by mesenchymal cells condensing into tissue elements(patterning phase) followed by their differentiation into cartilage(chondrocytes) or bone(osteoblasts) cells within the condensations. During the growth and remodeling phase, bone is formed directly via intramembranous ossification or through a cartilage to bone conversion via endochondral ossification routes. The canonical pathway of the endochondral bone formation process involves apoptosis of hypertrophic chondrocytes followed by vascular invasion that brings in osteoclast precursors to remove cartilage and osteoblast precursors to form bone. However, there is now an emerging role for chondrocyte-to-osteoblast transdifferentiation in the endochondral ossification process. Although the concept of "transdifferentiation" per se is not recent,new data using a variety of techniques to follow the fate of chondrocytes in different bones during embryonic and post-natal growth as well as during fracture repair in adults have identified three different models for chondrocyte-to-osteoblast transdifferentiation(direct transdifferentiation, dedifferentiation to redifferentiation, and chondrocyte to osteogenic precursor). This review focuses on the emerging models of chondrocyte-to-osteoblast transdifferentiation and their implications for the treatment of skeletal diseases as well as the possible signaling pathways that contribute to chondrocyte-to-osteoblast transdifferentiation processes. 展开更多
关键词 cartilage(chondrocytes)or bone(osteoblasts) chondrocyte-to-osteoblast
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