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Matrix stiffening promotes chondrocyte senescence and the osteoarthritis development through downregulating HDAC3

Bone Research 2024年第2期12卷 438-452页

作者： Bowen Fu Jianlin Shen xuenong zou Nian Sun Ze Zhang Zengping Liu Canjun Zeng Huan Liu Wenhua Huang Guangdong Medical Innovation Platform for Translation of 3D Printing Application The Third Affiliated HospitalSouthern Medical UniversityGuangzhou 510630 GuangdongChina Guangdong Engineering Research Center for Translation of Medical 3D Printing Application Guangdong Provincial Key Laboratory of Digital Medicine and BiomechanicsNational Key Discipline of Human AnatomySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510145 GuangdongChina Department of Foot and Ankle Surgery Center for Orthopedic SurgeryThe Third Affiliated HospitalSouthern Medical UniversityGuangzhou 510630 GuangdongChina Department of Orthopedics Affiliated Hospital of Putian UniversityPutian 351100 FujianChina Central Laboratory Affiliated Hospital of Putian UniversityPutian 351100 FujianChina Guangdong Provincial Key Laboratory of Orthopedics and Traumatology Department of Spinal SurgeryThe First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510080 GuangdongChina Nanfang Hospital Southern Medical UniversityGuangzhou 510515 GuangdongChina Guangzhou Blood Center Guangzhou 510095 GuangdongChina Department of Orthopedics The Affiliated Traditional Chinese Medicine HospitalSouthwest Medical UniversityLuzhou 646000 SichuanChina

Extracellular matrix(ECM)stiffening is a typical characteristic of cartilage aging,which is a quintessential feature of knee osteoarthritis(KOA).However,little is known about how ECM stiffening affects chondrocytes and other molecules *** study mimicked the physiological and pathological stiffness of human cartilage using polydimethylsiloxane(PDMS)*** demonstrated that epigenetic Parkin regulation by histone deacetylase 3(HDAC3)represents a new mechanosensitive mechanism by which the stiffness matrix affected chondrocyte *** found that ECM stiffening accelerated cultured chondrocyte senescence in vitro,while the stiffness ECM downregulated HDAC3,prompting Parkin acetylation to activate excessive mitophagy and accelerating chondrocyte senescence and osteoarthritis(OA)in ***,intra-articular injection with an HDAC3-expressing adeno-associated virus restored the young phenotype of the aged chondrocytes stimulated by ECM stiffening and alleviated OA in *** findings indicated that changes in the mechanical ECM properties initiated pathogenic mechanotransduction signals,promoted the Parkin acetylation and hyperactivated mitophagy,and damaged chondrocyte *** results may provide new insights into chondrocyte regulation by the mechanical properties of ECM,suggesting that the modification of the physical ECM properties may be a potential OA treatment strategy.

关键词： chondrocyte osteoarthritis stiffness

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Self-assemble peptide biomaterials and their biomedical applications

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Bioactive Materials 2019年第1期4卷 120-131页

作者： Jun Chen xuenong zou Department of Spine Surgery The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou510080PR China Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology Guangzhou510080PR China

Inspired by self-assembling peptides found in native proteins,deliberately designed engineered peptides have shown outstanding biocompatibility,biodegradability,and extracellular matrix-mimicking *** of the peptides can be triggered by external stimuli,such as electrolytes,temperature,and *** formation of nanostructures and subsequent nanocomposite materials often occur under physiological *** respective properties of side chains in each amino acids provide numerous sites for chemical modification and conjugation choices of the peptides,enabling various resulting supramolecular nanostructures and hydrogels with adjustable mechanical and physicochemical ***,additional functionalities can be easily induced into the hydrogels,including shearthinning,bioactivity,self-healing,and shape *** further broaden the scope of application of self-assemble peptide *** review outlines designs of self-assembly peptide(β-sheet,α-helix,collagen-like peptides,elastin-like polypeptides,and peptide amphiphiles)with potential additional functionalities and their biomedical applications in bioprinting,tissue engineering,and drug delivery.

关键词： properties. materials. biomaterials

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Bioadaptive Nanorod Topography of Titanium Surface to Control Cell Behaviors and Osteogenic Differentiation of Preosteoblast Cells

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Journal of Materials Science & Technology 2016年第9期32卷 944-949页

作者： Shao Xu Zhiyu Zhou Manman Gao Changye zou Yinglin Che Bünger Cody xuenong zou Lei Zhou Department of Stomatology The Third Affiliated Hospital of Southern Medical University Guangdong Provincial Key Laboratory of Orthopedics and Traumatology/Orthopedic Research Institute The First Affiliated Hospital of Sun Yat-sen University Department of Musculoskeletal Oncology The First Affiliated Hospital of Sun Yat-sen University Orthopaedic Research Laboratory Department of Orthopaedic Surgery Aarhus University Hospital Guangdong Provincial Stomatological Hospital Southern Medical University

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.

关键词： Titanium Nanorods Osteointegration Osteoblast differentiation

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Biosynthesis of Bioadaptive Materials:A Review on Developing Materials Available for Tissue Adaptation

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Journal of Materials Science & Technology 2016年第9期32卷 810-814页

作者： Junxuan Ma Zhiyu Zhou Manman Gao Binsheng Yu Deming Xiao xuenong zou Cody Bvnger Department of Orthopaedic Peking University Shenzhen HospitalShenzhen 518036China Department of Spinal Surgery/Orthopaedic Research Institute The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510080China Orthopaedic Research Lab/The Institute of Clinical Medicine Aarhus University Hospital8000 Aarhus CDenmark

Biomaterials are increasingly being evolved to actively adapt to the desired microenvironments so as to introduce tissue integration, reconstruct stability, promote regeneration, and avoid immune rejection. The complexity of its mechanisms poses great challenge to current biomimetic synthetic materials. Although still at initial stage, harnessing cells, tissues, or even entire body to synthesize bioadaptive materials is introducing a promising future.

关键词： Biomaterials Bioadaptation Tissue integration Biosynthesis

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Bone marrow adipoq+ cell population controls bone mass via sclerostin in mice

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Signal Transduction and Targeted Therapy 2023年第8期8卷 3570-3572页

作者： Huanqing Gao Yiming Zhong Sixiong Lin Qinnan Yan xuenong zou Guozhi Xiao Department of Biochemistry School of MedicineGuangdong Provincial Key Laboratory of Cell Microenvironment and Disease ResearchShenzhen Key Laboratory of Cell MicroenvironmentSouthern University of Science and TechnologyShenzhen 518055China State Key Laboratory of Genetic Engineering and School of Life Sciences Fudan UniversityShanghai 200438China Guangdong Provincial Key Laboratory of Orthopedics and Traumatology Department of Spinal SurgeryThe First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510080China

Dear editor,The comorbidity of obesity and osteoporosis illustrates the communication and coordination of adipose and bone *** and adiponectin derived from adipocytes regulate osteoblast formation and function to impact bone mass through direct and indirect mechanisms.1 It is known that bone marrow adipocytes(BMA)can control bone mass by modulating the bone morphogenetic protein(BMP)and other signaling *** can secret soluble factors,which impact osteoblasts,osteoclasts,and osteocytes.2 Sclerostin is a potent inhibitor of bone acquisition that antagonizes Wnt/β-catenin signaling.

关键词： marrow osteoporosis obesity

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Opposite Regulation of Chondrogenesis and Angiogenesis in Cartilage Repair ECM Materials under Hypoxia

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Journal of Materials Science & Technology 2016年第9期32卷 978-985页

作者： Shaoming Chen Manman Gao Zhiyu Zhou Jiabi Liang Ming Gong Xuejun Dai Tangzhao Liang Jiacheng Ye Gang Wu Lijin zou Yingjun Wang xuenong zou Orthopedic Department The Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhai 519000China Guangdong Provincial Key Laboratory of Orthopedics and Traumatology/Orthopedic Research Institute The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510075China Department of Spine Surgery The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510080China School of Materials Science and Engineering South China University of TechnologyGuangzhou 510640China National Engineering Research Center for Tissue Restoration and Reconstruction Guangzhou 510006China Department of Burn Surgery and Gastroenterology The First Affiliated Hospital of Nanchang UniversityNanchang 330000China

Although cartilage tissue engineering has been developed for decades, it is still unclear whether angio- genesis was the accompaniment of chondrogenesis in cartilage regeneration. This study aimed to explore the process of anti-angiogenesis during cartilage regenerative progress in cartilage repair extracellular matrix （ECM） materials under Hypoxia. C3H10T1/2 cell line, seeded as pellet or in ECM materials, was added with chondrogenic medium or DMEM medium for 21 days under hypoxia or normoxia environment. Genes and miRNAs related with chondrogenesis and angiogenesis were detected by RT-qPCR technique on Days 7, 14, and 21. Dual-luciferase report system was used to explore the regulating roles of miRNAs on angiogenesis. Results showed that the chondrogenic medium promotes chondrogenesis both in pellet and ECM materials culture. HIF1α was up-regulated under hypoxia compared with normoxia （P 〈 0.05）. Meanwhile, hypoxia enhanced chondrogenesis, miR-140-Sp exhibited higher expression while miR-146b exhibited lower expression. The chondrogenic phenotype was more stabilized in the ECM materials in chondrogenic medium than DMEM medium, with lower VEGFα expression even under hypoxia. Dual-luciferase report assays demonstrated that miR-140-5p directly targets VEGFct by binding its 3＇- UTR. Taken together, chondrogenic cytokines, ECM materials and hypoxia synergistically promoted chondrogenesis and inhibited angiogenesis, miR-140-5p olaved an imnortant role in this process.

关键词： Biomaterials Bio-adaptation Hypoxia Chondrogenesis Angiogenesis miRNAs

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An overview on bone protein extract as the new generation of demineralized bone matrix

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Science China(Life Sciences) 2012年第12期55卷 1045-1056页

作者： ZHOU ZhiYu zou LiJin LI HaiSheng BUNGER Cody zou xuenong IOrthopadic Research lnstttute/Department of Orthpaedic Surgery First Affiliated Hospital of Sun Yat-sen University Guangzhou 510080 China Department of Burn Surgery First Affiliated Hospital of Nanchang University Nanchang 330031 China Orthopaedic Research Laboratory/ Department of Orthpaedlc Surgery Aarhus University Hospital Aarhus 8000 Denmark

Bone protein extract is regarded as the new generation of demineralized bone matrix. The aim of this paper is to describe and characterize the properties of demineralized bone matrix and its new generation product in addition to its application in animal and human studies. Bone protein extract has features of osteoconductivity, osteoinductivity and osteogenicity, which originate from its unique and precise processing. It has exhibited powerful bone formation capacity both in animal experiments and in clinical trials by providing an optimal microenvironment for osteogenesis. Furthermore, not only does it have excellent bio- compatibility, it also has good compatibility with other implant materials, helping it bridge the host and implanted materials. Bone protein extract could be a promising alternative for demineralized bone matrix as a bone graft substitute.

关键词： bone protein extract demineralized bone matrix autologous bone graft osteogenesis

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Biomembrane-inspired design of medical micro/nanorobots:From cytomembrane stealth cloaks to cellularized Trojan horses

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Aggregate 2023年第5期4卷 63-95页

作者： Jinhua Li Huaijuan Zhou Chun Liu Shuailong Zhang Ran Du Yulin Deng xuenong zou School of Medical Technology Beijing Institute of TechnologyBeijingChina Advanced Research Institute of Multidisciplinary Sciences Beijing Institute of TechnologyBeijingChina Center for Translational Medicine Precision Medicine InstituteThe First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina Guangdong Provincial Key Laboratory of Orthopedics and Traumatology Department of Spinal SurgeryThe First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina School of Mechatronical Engineering Beijing Institute of TechnologyBeijingChina School of Materials Science&Engineering Key Laboratory of High Energy Density Materials of the Ministry of EducationBeijing Institute of TechnologyBeijingChina School of Life Science Beijing Institute of TechnologyBeijingChina

Micro/nanorobots are promising for a wide range of biomedical applications(such as targeted tumor,thrombus,and infection therapies in hard-to-reach body sites)because of their tiny size and high maneuverability through the actuation of external fields(e.g.,magnetic field,light,ultrasound,electric field,and/or heat).However,fully synthetic micro/nanorobots as foreign objects are susceptible to phagocytosis and clearance by diverse *** address this issue,researchers have attempted to develop various cytomembrane-camouflaged micro/nanorobots by two means:(1)direct coating of micro/nanorobots with cytomembranes derived from living cells and(2)the swallowing of micro/nanorobots by living immunocytes via *** camouflaging with cytomembranes or living immunocytes not only protects micro/nanorobots from phagocytosis,but also endows them with new characteristics or functionalities,such as prolonging propulsion in biofluids,targeting diseased areas,or neutralizing bacterial *** this review,we comprehensively summarize the recent advances and developments of cytomembrane-camouflaged medical micro/*** first discuss how cytomembrane coating nanotechnology has been employed to engineer synthetic nanomaterials,and then we review in detail how cytomembrane camouflage tactic can be exploited to functionalize micro/*** aim to bridge the gap between cytomembrane-cloaked micro/nanorobots and nanomaterials and to provide design guidance for developing cytomembrane-camouflaged micro/nanorobots.

关键词： camouflage cell membranes immune cells medical micromotors targeted drug delivery

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Synergistic osteogenic and angiogenic effects of KP and QK peptides incorporated with an injectable and self-healing hydrogel for efficient bone regeneration

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Bioactive Materials 2022年第12期7卷 267-283页

作者： Runze Li Chen Zhou Jun Chen Haotian Luo Ruoyu Li Danying Chen xuenong zou Weicai Wang Hospital of Stomatology Guanghua School of StomatologyGuangdong Provincial Key Laboratory of StomatologySun Yat-sen University56 Lingyuanxi RoadGuangzhou510055China Department of Organ Transplantation Zhujiang HospitalSouthern Medical UniversityGuangzhou510280China The Key Laboratory of Imflammation and Autoimmune Diseases Guangzhou510280China Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology Department of Spine SurgeryThe First Affiliated HospitalSun Yat-sen UniversityGuangzhou510080China

Irregular defects generated by trauma or surgery in orthopaedics practice were usually difficult to be fitted by the preformed traditional bone graft substitute. Therefore, the injectable hydrogels have attracted an increasing interest for bone repair because of their fittability and mini-invasivity. However, the uncontrollable spreading or mechanical failures during its manipulation remain a problem to be solved. Moreover, in order to achieve vascularized bone regeneration, alternatives of osteogenic and angiogenic growth factors should be adopted to avoid the problem of immunogenicity and high cost. In this study, a novel injectable self-healing hydrogel system (GMO hydrogel) loaded with KP and QK peptides had been developed for enhancing vascularized regeneration of small irregular bone defect. The dynamic imine bonds between gelatin methacryloyl and oxidized dextran provided the GMO hydrogel with self-healing and shear-thinning abilities, which led to an excellent injectability and fittability. By photopolymerization of the enclosed GelMA, GMO hydrogel was further strengthened and thus more suitable for bone regeneration. Besides, the osteogenic peptide KP and angiogenic peptide QK were tethered to GMO hydrogel by Schiff base reaction, leading to desired releasing profiles. In vitro, this composite hydrogel could significantly improve the osteogenic differentiation of BMSCs and angiogenesis ability of HUVECs. In vivo, KP and QK in the GMO hydrogel demonstrated a significant synergistic effect in promoting new bone formation in rat calvaria. Overall, the KP and QK loaded GMO hydrogel was injectable and self-healing, which can be served as an efficient approach for vascularized bone regeneration via a minimally invasive approach.

关键词： Injectable hydrogel Self-healing KP peptide QK peptide Bone tissue engineering

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Biomimetic hydroxyapatite coating on the 3D-printed bioactive porous composite ceramic scaffolds promoted osteogenic differentiation via PI3K/AKT/mTOR signaling pathways and facilitated bone regeneration in vivo

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Journal of Materials Science & Technology 2023年第5期136卷 54-64页

作者： Bizhi Tan Naru Zhao Wei Guo Fangli Huang Hao Hu Yan Chen Jungang Li Zemin Ling Zhiyuan zou Rongcheng Hu Chun Liu Tiansheng Zheng Gang Wang Xiao Liu Yingjun Wang xuenong zou Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology Department of Spine SurgeryThe First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510080China School of Materials Science and Engineering South China University of TechnologyGuangzhou 510641China National Engineering Research Center for Tissue Restoration and Reconstruction Guangdong Province Key Laboratory of Biomedical EngineeringSouth China University of TechnologyGuangzhou 510006China Department of Orthopedics The First Affiliated Hospital of Gannan Medical UniversityGanzhou 341000China

The architecture and surface modifications have been regarded as effective methods to enhance the bi-ological response of biomaterials in bone tissue *** porous architecture of the implanta-tion was essential conditions for bone ***,the design of biomimetic hydroxyap-atite(HAp)coating on porous scaffolds was demonstrated to strengthen the bioactivity and stimulate ***,bioactive bio-ceramics such asβ-tricalcium phosphate(β-TCP)and calcium sili-cate(CS)with superior apatite-forming ability were reported to present better osteogenic activity than that of *** in this study,3D-printed interconnected porous bioactive ceramicsβ-TCP/CS scaf-fold was fabricated and the biomimetic HAp apatite coating were constructed in situ via hydrothermal reaction,and the effects of HAp apatite layer on the fate of mouse bone mesenchymal stem cells(mBM-SCs)and the potential mechanisms were *** results indicated that HAp apatite coating en-hanced cell proliferation,alkaline phosphatase(ALP)activity,and osteogenic gene ***-more,PI3K/AKT/mTOR signaling pathway is proved to have an important impact on cellular *** present results demonstrated that the key molecules of phosphatidylinositol 3-kinase(PI3K),protein kinase B(AKT)and mammalian target of rapamycin(mTOR)were activated after the biomimetic hydrox-yapatite coating were constructed on the 3D-printed ceramic ***,the activated influence on the protein expression of Runx2 and BMP2 could be suppressed after the treatment of inhibitor *** vivo studies showed that the constructed HAp coating promoted bone formation and strengthen the bone *** results suggest that biomimetic HAp coating constructed on the 3D-printed bioac-tive composite scaffolds could strengthen the bioactivity and the obtained biomimetic multi-structured scaffolds might be a potential alternative bone graft for bone regeneration.

关键词： Bioactive ceramics Hydroxyapatite coating 3D-printed porous ceramic scaffold PI3K/AKT/mTOR signaling pathway Bone regeneration

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