JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2020
·Vol. 24
·期 21
·12476-12490
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IF 4.486
Zhongping Su,Pengyu Zong,Ji Chen,Shuo Yang,Yihui Shen,Yan Lu,Chuanxi Yang,Xiangqing Kong,Yanhui Sheng,Wei Sun
Vascular calcification is an important risk factor for the mortality and morbidity in chronic kidney disease (CKD). Unfortunately, until now there is no certain medication targeting vascular calcification in CKD. In this study, we explored the inhibitory effect of celastrol on high calcium–induced vascular calcification and the underlying molecular mechanisms. Cell proliferation assay showed that celastrol inhibited aortic valve interstitial cell (VIC) and vascular smooth muscle cell (VSMC) proliferation when its concentration was higher than 0.6 μmol/L. 0.8 μmol/L celastrol inhibited the expression of osteogenic genes and calcium deposition induced by high-calcium medium in both AVICs and VSMCs. In mouse vascular calcification model induced by adenine combined with vitamin D, alizarin red and immunostaining showed that celastrol inhibited pro-calcification gene expression and calcium deposition in aortic wall and aortic valve tissues. At the molecular level, celastrol inhibited the increase of BMP2, phosphorylated Smad1/5 (p-Smad1/5) and non-phosphorylated β-catenin (n-p-β-catenin) induced by high-calcium medium both in vitro and in vivo. Also, BMP2 overexpression reversed the anti-calcification effects of celastrol by recovering the decrease of p-Smad1/5 and n-p-β-catenin. Furthermore, celastrol prevented the up-regulation of BMPRII and down-regulation of Smad6 induced by high calcium, and this protectory effect can be abolished by BMP2 overexpression. In conclusion, our data for the first time demonstrate that celastrol attenuates high calcium–induced arterial and valvular calcification by inhibiting BMP2/Smad1/5 signalling, which may provide a novel therapeutic strategy for arterial and valvular calcification in patients with CKD.
研究领域:
药理学
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心血管疾病
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肾病学
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分子生物学
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PubMed
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Stem Cell Research & Therapy
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2025
·Vol. 16
·期 1
·691
·
IF 7.3
Gu Hongji,Liu Buhan,An Yue
Background Bone marrow mesenchymal stem cells (BMSCs) play a crucial role in bone repair and regeneration. The sirtuin family member sirtuin 5 (SIRT5) has been implicated in various cellular processes, including the regulation of osteogenic differentiation. This study aimed to investigate the role of SIRT5 in osteogenic differentiation of BMSCs and its impact on fracture healing. Methods BMSCs were characterized and induced to undergo osteogenic and adipogenic differentiation. The effects of SIRT5 modulation on osteogenic differentiation were assessed through alkaline phosphatase (ALP) staining, Alizarin Red S (ARS) staining, and osteogenic genes expression analysis. The role of SIRT5 in regulating bone morphogenetic protein 2 (BMP2) succinylation and stability was explored using Western blot, immunoprecipitation, and co-immunoprecipitation. A rat tibial fracture model was used to evaluate the in vivo effects of SIRT5 and BMP2 modulation on fracture healing, assessed by Micro-CT and histological analysis. Results SIRT5 overexpression enhanced osteogenic differentiation of BMSCs, as evidenced by increased ALP activity and mineralization. It also upregulated the expression of osteogenic markers such as osteopontin (OPN), runt-related transcription factor 2 (RUNX2), osterix (OSX), and BMP2. Conversely, SIRT5 knockdown inhibited these processes. Mechanistically, SIRT5 was found to regulate BMP2 succinylation, affecting its stability and function. In vivo, overexpression of SIRT5 in a rat tibial fracture model significantly improved bone volume fraction, trabecular number, and thickness, while reducing trabecular separation. The beneficial effects of SIRT5 overexpression were counteracted by BMP2 knockdown, highlighting the importance of BMP2 in mediating SIRT5’s actions on bone healing. Conclusion SIRT5 promotes osteogenic differentiation of BMSCs and enhances fracture healing by modulating BMP2 succinylation. These findings suggest that SIRT5 could be a potential therapeutic target for the treatment of bone fractures and other skeletal disorders.
研究领域:
分子生物学
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干细胞研究
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骨再生医学
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翻译后修饰
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Communications Biology
·
2026
·
IF 5.1
Zheng Zhichao,Li Xingyang,Qin Wenguang,Yu Shuiqing,Xu Tianru,Cheng Haoyu,Xie Wei,Fu Zhihe,Pan Guokai,Zhang Yuhui,Huang Wenyan,Liu Fei,Jiang Yifan,Jaspers Richard T.,Pathak Janak L.,Wu Lihong
Non-coding RNAs, including piwi-interacting RNAs (piRNAs), are known to regulate osteogenic differentiation in bone marrow-derived mesenchymal stem cells (BMSCs); their role in mesenchymal stem cells (MSCs) from diverse origins remains unclear. In this study, we identified piR48444 as a key regulator that is downregulated during the osteogenic differentiation of stem cells from exfoliated deciduous teeth (SHED) but is upregulated in inflamed and aged BMSCs. Functionally, piR48444 inhibited, while its knockdown enhanced osteogenic differentiation across MSCs from multiple sources. Notably, piR48444-depleted MSCs exhibited superior bone defect repair capacity. PiR48444 antagomir promoted bone regeneration in LPS-induced osteolysis mice and aging mice. Mechanistically, we demonstrated that piR48444 targets METTL7A , suppressing BMP2 mRNA m 6 A methylation. Furthermore, we discovered that the METTL7A/eIF4E complex binds to BMP2 mRNA, thereby enhancing its translational efficiency. Our findings establish piR48444 as a negative regulator of MSC osteogenesis through METTL7A-mediated BMP2 m 6 A methylation, highlighting its potential as a therapeutic target to enhance MSC-based bone regeneration strategies.
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CHEMICAL ENGINEERING JOURNAL
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2021
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IF 13.273
Zhuo Liang,Li Yang,Yonggang Lv
Gene therapy based on non-viral vector has been used to promote the repair of bone damage. However, low transfection efficiency and uncontrollable expression greatly hinder its clinical translation. Exosomes (Exos) have been extensively studied as a promising non-viral delivery carrier recently, while its delivery efficiency for large nucleic acids is low. Here, a novel gene vector was developed by layer-by-layer self-assembly method using polyethyleneimine (PEI) and Exos derived from mesenchymal stem cells (MSCs) to deliver large plasmids efficiently. Moreover, a hypoxia-specific expression plasmid was constructed by combining hypoxia promoter RTP801 and microRNA 877 (miR877) sponge. Experimental results showed that the gene delivery vector based on Exos exhibited high transfection efficiency and low cytotoxicity to MSCs. The hypoxia-specific expression plasmid significantly increased bone morphogenetic protein 2 ( BMP2 ) expression in hypoxic condition and promoted neoangiogenesis. This study may provide a novel method to improve the repair efficiency in bone tissue engineering.
研究领域:
基因治疗
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组织工程
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干细胞生物学
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骨再生
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CARBOHYDRATE POLYMERS
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2021
·
IF 9.381
Lei Xu,Fenbo Ma,Frankie K.L. Leung,Chenghe Qin,William W. Lu,Bin Tang
Bone defects caused by trauma have become increasingly common in aged populations. Clinically, because of the relatively decreased bone healing capacity compared with the youth adults, bone defect repair in the elderly remains challenging. The development of effective biomaterials targeted at bone defects in the elderly is a key component of bone-tissue engineering strategies. However, little attention has been paid to bone regeneration in the elderly. Here, we developed a new scaffold chitosan-Strontium chondroitin sulfate (CH-SrCS) and evaluated its effect on improving bone regeneration. We find that the CH-SrCS scaffold displayed positive effects on downregulation of inflammation and osteoclastogenesis related mRNA expressions while demonstrating a significant increase in the expression level of BMP2. Finally, we show that the bone defects healing effects as assessed using an aged rats' bone defects model. Ultimately, this work also provides insights into the design of effective biomaterials targeted at bone defects in the elderly.
研究领域:
生物医学工程
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骨组织工程
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老年医学
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DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2019
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IF 3.973
Bailong Tao,Yiman Deng,Liying Song,Wenwen Ma,Ying Qian,Chuanchuan Lin,Zhang Yuan,Lu Lu,Maowen Chen,Xin Yang,Kaiyong Cai
Bacterial infection and surface biointertness are two main causes for titanium (Ti)-based orthopedic implants failure. To improve the antibacterial ability and enhance poor osteogenic property of Ti substrates, in this work, we employed titania nanotubes (TNTs) as Bone Morphogenetic Protein 2 (BMP2) carrier, and a pH-responsive multilayer film composed of alginate dialdehyde-gentamicin (ADA-Gen) and chitosan (Chi) was constructed onto BMP2-loaded TNTs substrates through layer-by-layer (LBL) assembly technique, resulting in TNT-BMP2-LBLg samples. The release experiments revealed that acidic environment could trigger the release of Gen from the multilayer films and in turn accelerate the release of BMP2 from TNTs. Moreover, antibacterial assay against E. coli and S. aureus confirmed that the TNT-BMP2-LBLg had excellent antibacterial capacity both in early (6 h) and in long-term (72 h). Meanwhile, in vitro cellular tests demonstrated that TNT-BMP2-LBLg had good cytocompatibility toward osteoblasts even co-cultured with S. aureus . Importantly, the obtained TNT-BMP2-LBLg promoted differentiation of osteoblasts, including enhanced alkaline phosphatase activity, improved mineralization capability and stimulated osteogenic-relative gene expression. This study thus provides a promising strategy to develop pH-responsive antibacterial and enhance bone integrative Ti-based implants for potential orthopedic application.
研究领域:
生物医学工程
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材料科学
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骨科医学
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DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
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2026
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IF 5.8
Lin Zhang,Mengxia Chen,Zhen Chen,Sunfei Chen,Shenghan Duan,Shuqi Lou,Hongsheng Wang
Introduction Bone tissue engineering requires scaffolds that mimic the native extracellular matrix and provide sustained delivery of osteoinductive factors. This study focuses on developing a multifunctional scaffold using a green electrospinning process to combine the biocompatibility of silk fibroin (SF) with a non‐viral gene delivery system for sustained expression of Bone Morphogenetic Protein 2 (BMP2). Methods A green electrospinning technique, using an aqueous SF and polyethylene oxide (PEO) solution, was employed to fabricate nanofibrous scaffolds, eliminating the use of harsh organic solvents. Polyethylenimine (PEI) modified liposomes (Lipo PEI ) were used to encapsulate a BMP2‐encoding plasmid (pDNA Bmp2 ). These gene‐loaded nanoparticles were incorporated into the SF‐PEO nanofibers. The resulting scaffolds were characterized for morphology (SEM), structure (FTIR, XRD), and drug release kinetics. Biological performance was evaluated by assessing cell viability (MTT assay), cell attachment (SEM), gene transfection efficiency (confocal microscopy), and osteogenic differentiation (alkaline phosphatase (ALP) activity, Alizarin Red S staining) using bone marrow mesenchymal stem cells (BMSCs). Results Physicochemical characterization confirmed the successful formation of uniform pDNA Bmp2 @Lipo PEI nanocomplexes with a particle size of approximately 266 nm and a positive surface charge of +16.9 mV. These nanocomplexes were homogeneously incorporated into smooth, bead-free SF‐PEO nanofibers with average diameters ranging from 460 to 541 nm. The composite scaffold demonstrated a highly sustained release of pDNA Bmp2 over 14 days. In vitro studies using rat bone marrow-derived mesenchymal stem cells (BMSCs) revealed that the scaffold possesses excellent biocompatibility, promoting robust cell adhesion, spreading, and proliferation. Furthermore, the gene‐loaded scaffold successfully mediated the transfection of BMSCs, leading to significant upregulation of osteogenic markers, including alkaline phosphatase (ALP) activity and extensive calcium mineral deposition over 21 days. Discussion The novel composite scaffold combines the structural advantages of SF with a sustained BMP2 gene delivery system, showing remarkable potential to promote osteogenic differentiation. This work presents a promising, environmentally friendly, and effective platform for bone tissue engineering and regenerative medicine.
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高影响因子
CytoJournal
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2025
·
IF 3.1
Xunjia Li,Zhixin Xu,Ying Li,Yan Luo,Jie Zhou,Deyu Zuo,Weijian Xiong
Objective:
Patients with chronic kidney disease (CKD) exhibit increased vascular calcification (VC) risks, worsened by high-dose erythropoietin (EPO). While EPO treats anemia, its role in VC pathogenesis remains unclear. Ginsenoside Rb1 (Rb1), a Panax ginseng compound with anti-calcification properties, may counteract EPO-induced VC through the GATA binding protein 6 (GATA6)/bone morphogenetic protein 2 (BMP2)/Smad1/5/9 pathway. This article aims to explore whether Rb1 could counteract EPO-induced VC through the GATA6/BMP2/Smad1/5/9 pathway.
Material and Methods:
Adenine-induced CKD rats and b-glycerophosphate-treated vascular smooth muscle cells (VSMCs) received EPO ± Rb1. Calcification was assessed through von Kossa/alizarin red staining. Smooth muscle protein 22-a (SM22a)/a-Smooth muscle actin (a-SMA) expression was measured by immunofluorescence and real-time-quantitative polymerase chain reaction (RT-qPCR). GATA6/BMP2/Smad1/5/9 activation was analyzed using RT-qPCR/Western blot. Rb1-BMP2 interactions were tested through biotin pulldown, micro-thermophoresis, and Co-immunoprecipitation (Co-IP). GATA6 knockdown validated pathway roles.
Results:
High-dose EPO significantly worsened CKD-associated calcification and VSMC calcification (P < 0.01), suppressed SM22a and a-SMA expression levels, and activated the GATA6/BMP2/Smad1/5/9 pathway (P < 0.01). GATA6 knockdown reduced EPO-exacerbated calcification and modulated BMP2/Smad1/5/9 signaling (P < 0.01). Rb1 increased SM22a and a-SMA expression levels and inhibited Smad 1/5/9 phosphorylation (P < 0.01), without affecting GATA6 or BMP2 expression (P > 0.05). Molecular docking and Co-IP experiments revealed that Rb1 binds directly to BMP2, blocking its interaction with bone morphogenetic protein receptor and inhibiting Smad 1/5/9 phosphorylation (P < 0.01).
Conclusion:
Rb1 mitigates EPO-aggravated VC in CKD by disrupting BMP2/Smad1/5/9 signaling, positioning it as a promising molecular intervention strategy to reduce EPO-induced vascular toxicity.
Keywords: Bone morphogenetic protein 2/Smad1/5/9 signaling pathway, Chronic kidney disease, Erythropoietin, Ginsenoside Rb1, Vascular calcification
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Bioactive Materials
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2020
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IF 8.724
Minqi Wang,Hanjun Li,Yiqi Yang,Kai Yuan,Feng Zhou,Haibei Liu,Qinghui Zhou,Shengbing Yang,Tingting Tang
Large bone defects face a high risk of pathogen exposure due to open wounds, which leads to high infection rates and delayed bone union. To promote successful repair of infectious bone defects, fabrication of a scaffold with dual functions of osteo-induction and bacterial inhibition is required. This study describes creation of an engineered progenitor cell line (C3H10T1/2) capable of doxycycline (DOX)-mediated release of bone morphogenetic protein-2 (BMP2). Three-dimensional bioprinting technology enabled creation of scaffolds, comprising polycaprolactone/mesoporous bioactive glass/DOX and bioink, containing these engineered cells. In vivo and in vitro experiments confirmed that the scaffold could actively secrete BMP2 to significantly promote osteoblast differentiation and induce ectopic bone formation. Additionally, the scaffold exhibited broad-spectrum antibacterial capacity, thereby ensuring the survival of embedded engineered cells when facing high risk of infection. These findings demonstrated the efficacy of this bioprinted scaffold to release BMP2 in a controlled manner and prevent the occurrence of infection; thus, showing its potential for repairing infectious bone defects.
研究领域:
组织工程
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再生医学
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生物医学工程
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细胞生物学
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
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2022
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IF 11.092
Wan Ting Sow,Yili Wang,Liping Chen,Qiling Lai,Qiong Chen,Linjie Chen,Chunwu Zhang,Huaqiong Li
An ideal bone regenerative scaffold is expected to possess architectural characteristics that mimic the bone tissue, osteoconductive properties, and osteoinductive functionality. Key challenges to creating a scaffold with these ideal characteristics simultaneously are the selection of appropriate processing methods and biocompatible materials. Herein, human hair keratin is proposed as an organic binder for the simultaneous incorporation of bone's major inorganic component, hydroxyapatite and bone's growth factor, recombinant human bone morphogenetic protein 2 (rhBMP2) to enable both osteoconductive and osteoinductive characteristics in the creation of bone scaffolds. Furthermore, a freeze-casting method is selected to fabricate this rhBMP2-incorporated keratin/hydroxyapatite (KHA) scaffold with aligned lamellar pores to guide and promote bone regeneration. The aligned KHA scaffolds display better mechanical properties, sustained rhBMP2 release, good cell compliance, and 3D cellular infiltration. Implantation of KHA scaffolds in vivo reveals that scaffolds with aligned pores effectively accelerate the healing process of bone defects compared to scaffolds with random pores. This work indicates the distinctive potential of freeze-casted rhBMP-2 incorporated KHA scaffolds for bone regeneration.
研究领域:
生物医学工程
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组织工程
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材料科学
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骨科
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PubMed
高影响因子
ACS Applied Materials & Interfaces
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2018
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IF 8.097
Miusi Shi,Ruiwen Yang,Qin Li,Kangle Lv,Richard J. Miron,Jie Sun,Mei Li,Yufeng Zhang
Since the discovery of osteoinduction in the early 20th century, innovative biomaterials with osteoinductive potential have emerged as candidates for bone repair. Recently, artificial protocell models have demonstrated great potential for tissue regeneration. Herein, we developed artificial bioactive proto-osteocells by self-assembly of biodegradable biphasic-phosphate particles in the form of aqueous bone morphogenetic protein 2 (BMP2)-containing Pickering emulsions in corn oil to fulfill the release of BMP2 with controlled and local efficacy. These artificial proto-osteocells have the advantage of (1) being directly injected into the target location to avert reported side effects of BMP2, minimizing surgical complications, (2) exhibiting the capability of osteoinduction as shown in both in vitro and in vivo models, and (3) demonstrating calcific deposition locally by utilizing the biodegradable calcium phosphate shell. The efficiency of BMP2 within the artificial proto-osteocells showed 25 times greater bone-inducing potential when compared to the control. This study demonstrates for the first time a new strategy toward utilizing material-based artificial proto-osteocells to tackle medical issues in bone tissue repair and regeneration.
研究领域:
生物医学工程
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组织工程
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生物材料科学
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DOI
PubMed
高影响因子
American Journal of Translational Research
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2020
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IF 3.375
Runzi Gao,Wenhui Ji,Tianwei Xia,Yanxing Fan,Wei Wei,Le Shi,Jinzhu Liu,Chao Zhang,Lezhen Xue,Jirong Shen
Osteonecrosis of the femoral head (ONFH) is a common disorder that may be idiopathic, caused by trauma, or associated with alcohol or glucocorticoid use. The goals of early treatment include delaying or avoiding hip replacement, but there are no effective treatments for early-stage disease. The aim of the present study was to evaluate the effects of treatment with 3D-printed porous titanium alloy scaffold combined with daily intraperitoneal trans-cinnamaldehyde (TCA) in a dog model of ONFH. Four weeks after creation of the ONFH model, MRI examination of the femoral head showed the characteristic “double line sign” of ONFH, verifying the validity of our model. After another 12 weeks, femoral head specimens were harvested and examined by gross inspection; micro-computed tomography; histologic staining (hematoxylin and eosin; Masson); immunohistochemical analysis and quantitative real-time polymerase chain reaction analysis. Gross inspection of the femoral head in untreated ONFH animals at 16 weeks after model creation showed pale, exfoliating articular cartilage and disordered trabecular bone. Treatment with 3D-printed titanium alloy porous scaffold combined with TCA ameliorated the pathologic ONFH changes and significantly reduced inmature bone tissue as well as imature collagen in the femoral head, as shown by Masson staining. This treatment also increased VEGF, BMP2, β-catenin, b-FGF, and RUNX2 expression and decreased PPARγ expression, compared with untreated ONFH. In conclusion, 3D-printed titanium alloy porous scaffold combined with TCA can effectively improve ONFH, which may be related to local repair. This provides the theoretical basis for a new treatment strategy for ONFH.
研究领域:
骨科
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再生医学
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药理学
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生物医学工程
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PubMed
高影响因子
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