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Novel strategies for the treatment of osteoarthritis based on biomaterials and critical molecular signaling

Journal of Materials Science & Technology 2023年第18期149卷 42-55页

作者： Xingyun Huang Zhiyong Wang Huaiyu Wang Di Chen liping tong Research Center for Computer-aided Drug Discovery Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Faculty of Pharmaceutical Sciences Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China University of Chinese Academy of Sciences Beijing 100049China Center for Human Tissues and Organs Degeneration Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China

Osteoarthritis(OA)is a degenerative disease involving entire joint.It is often initiated from the low-grade inflammation in synovial tissue and then affects articular cartilage and subchondral bone.Multiple risk factors,such as aging,mechanical overloading,trauma,overuse,etc.are involved in OA development.Several approaches have been utilized to repair cartilage defects.Among them,biomaterials-based mes-enchymal stromal cell(MSCs)therapy is considered as the most promising modality.The burgeoning material science and manufacturing technologies,such as 3D printing,allow us to mimic native articu-lar cartilage and regulate the artificial cartilage development,regeneration and functional restoration.In this review article,we will summarize the recent progress of biomaterials combined with MSCs or chon-drocytes in repairing cartilage damage induced by OA.Several typical natural and synthetic biomaterials,such as collagen,alginate,hyaluronic acid and poly(ethylene glycol),polylactide acid,polyurethane,etc.for cartilage repairing will be introduced.Moreover,critical signaling pathways associated with the pro-gression of OA,as well as the targeted pharmacologic,genetic therapies and tissue engineering scaffolds for OA and cartilage repairing are presented.We will also provide our prospects for future directions in this active research area.

关键词： Osteoarthritis Cartilage Repairing Biomaterials 3D printing Signaling pathways

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Risk of metabolic abnormalities in osteoarthritis:a new perspective to understand its pathological mechanisms

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Bone Research 2023年第4期11卷 679-694页

作者： Guizheng Wei Ke Lu Muhammad Umar Zhenglin Zhu William WLu John RSpeakman Yan Chen liping tong Di Chen Department of Bone and Joint Surgery the First Affiliated Hospital of Guangxi Medical UniversityNanning 530021China Research Center for Computer-aided Drug Discovery Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Faculty of Pharmaceutical Sciences Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Department of Orthopedic Surgery the First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Center for Energy Metabolism and Reproduction Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China

Although aging has traditionally been viewed as the most important risk factor for osteoarthritis(OA),an increasing amount of epidemiological evidence has highlighted the association between metabolic abnormalities and OA,particularly in younger individuals.Metabolic abnormalities,such as obesity and typeⅡdiabetes,are strongly linked to OA,and they affect both weightbearing and non-weight-bearing joints,thus suggesting that the pathogenesis of OA is more complicated than the mechanical stress induced by overweight.This review aims to explore the recent advances in research on the relationship between metabolic abnormalities and OA risk,including the impact of abnormal glucose and lipid metabolism,the potential pathogenesis and targeted therapeutic strategies.

关键词： metabolism pathogenesis osteoarthritis

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Rational multivalency construction enables bactericidal effect amplification and dynamic biomaterial design

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The Innovation 2023年第5期4卷 59-68页

作者： Xu Chen Xinrui Li Wenbo He Miao Wang Ang Gao liping tong Shun Guo Huaiyu Wang Guoqing Pan Institute for Advanced Materials School of Materials Science and EngineeringJiangsu UniversityZhenjiang 212013China Institute of Biomedicine and Biotechnology Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China

The multivalency of bioligands in living systems brings inspiration for not only the discovery of biological mechanisms but also the design of extracellular matrix(ECM)-mimicking biomaterials.However,designing controllable multivalency construction strategies is still challenging.Herein,we synthesized a series of well-defined multivalent antimicrobial peptide polymers(mAMPs)by clicking ligand molecules onto polymers prepared by reversible addition-fragmentation chain transfer polymerization.The multiple cationic ligands in the mAMPs could enhance the local disturbance of the anionic phospholipid layer of the bacterial membrane through multivalent binding,leading to amplification of the bactericidal effect.In addition to multivalency-enhanced antibacterial activity,mAMPs also enable multivalency-assisted hydrogel fabrication with an ECM-like dynamic structure.The resultant hydrogel with self-healing and injectable properties could be successfully employed as an antibacterial biomaterial scaffold to treat infected skin wounds.The multivalency construction strategy presented in this work provides new ideas for the biomimetic design of highly active and dynamic biomaterials for tissue repair and regeneration.

关键词： healing enable dynamic

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miR-204 ameliorates osteoarthritis pain by inhibiting SP1-LRP1 signaling and blocking neuro-cartilage interaction

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Bioactive Materials 2023年第8期26卷 425-436页

作者： Ke Lu Qingyun Wang Liuzhi Hao Guizheng Wei Tingyu Wang William WLu Guozhi Xiao liping tong Xiaoli Zhao Di Chen Research Center for Computer-aided Drug Discovery Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen518055China Faculty of Pharmaceutical Sciences Shenzhen Institute of Advanced TechnologyShenzhen518055China Research Center for Human Tissues and Organs Degeneration Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen518055China Department of Pharmacy Shanghai Ninth People’s HospitalShanghai Jiao-Tong University School of MedicineShanghai200011China Department of Orthopaedics and Traumatology The University of Hong KongHong Kong 999077China School of Medicine Southern University of Science and TechnologyShenzhen518055China

Osteoarthritis(OA)is a painful degenerative joint disease and is the leading cause of chronic disability among elderly individuals.To improve the quality of life for patients with OA,the primary goal for OA treatment is to relieve the pain.During OA progression,nerve ingrowth was observed in synovial tissue and articular cartilage.These abnormal neonatal nerves act as nociceptors to detect OA pain signals.The molecular mechanisms for transmitting OA pain in the joint tissues to the central nerve system(CNS)is currently unknown.MicroRNA miR-204 has been demonstrated to maintain the homeostasis of joint tissues and have chondro-protective effect on OA pathogenesis.However,the role of miR-204 in OA pain has not been determined.In this study,we investigated interactions between chondrocytes and neural cells and evaluated the effect and mechanism of miR-204 delivered by exosome in the treatment of OA pain in an experimental OA mouse model.Our findings demonstrated that miR-204 could protect OA pain by inhibition of SP1-LDL Receptor Related Protein 1(LRP1)signaling and blocking neuro-cartilage interaction in the joint.Our studies defined novel molecular targets for the treatment of OA pain.

关键词： miR-204 LRP1 Neuro-cartilage interaction Osteoarthritis Pain

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Aptamer-Based Cell-Surface Profiling with Single-Cell Resolution Enables Precise Cancer Characterization

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CCS Chemistry 2024年第1期6卷 196-207页

作者： Liujun Xu Yawei Feng tong Wang Shenhuan Li Kangli Xu Yue Sun Yi Luo Yishan Ye Yan Miao Yun Dong Zhenzhen Guo Qing Zhang Benshang Li He Huang Xue-Qiang Wang liping Qiu Weihong Tan Molecular Science and Biomedicine Laboratory State Key Laboratory of Chemo/Biosensing and ChemometricsCollege of Chemistry and Chemical EngineeringCollege of BiologyAptamer Engineering Center of Hunan ProvinceHunan UniversityChangshaHunan 410082 The Key Laboratory of Zhejiang Province for Aptamers and Theranostics Zhejiang Cancer HospitalHangzhou Institute of MedicineChinese Academy of SciencesHangzhouZhejiang 310022 Institute of Molecular Medicine Renji HospitalShanghai Jiao Tong University School of MedicineCollege of Chemistry and Chemical EngineeringShanghai Jiao Tong UniversityShanghai 200240 Bone Marrow Transplantation Center The First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310003 Institute of Hematology Zhejiang UniversityHangzhou 310003 Department of Hematology and Oncology Shanghai Children’s Medical CenterShanghai Jiao Tong University School of MedicineShanghai Jiao Tong UniversityShanghai 200127

Molecular profiling of cell-surface proteins is a powerful strategy for precise cancer diagnosis.While mass cytometry(MC)enables synchronous detection of over 40 cellular parameters,its full potential in disease classification is challenged by the limited types of recognition probes currently available.In this work,we synthesize a panel of heavy isotopeconjugated aptamers to profile cancer-associated signatures on the surface of hematological malignancy(HM)cells.Based on 15 molecular signatures,we performed cell-surface profiling that allowed the precise classification of 8 HM cell lines.Combined with machine-learning technology,this aptamer-based MC platform also achieved multiclass identification of HM subtypes in clinical sampleswith 100%accuracy in the training cohort and 80%accuracy in the test cohort.Therefore,we report an effective and practical strategy for precise cancer classification at the singlecell level,paving the way for its clinical use in the near future.

关键词： molecular profiling cancer diagnosis mass cytometry aptamers machine learning

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Upregulation of β-catenin signaling represents a single common pathway leading to the various phenotypes of spinal degeneration and pain

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Bone Research 2023年第2期11卷 316-327页

作者： Ke Lu Qingyun Wang Hua Jiang Jun Li Zhou Yao Yongcan Huang Jianquan Chen Yejia Zhang Guozhi Xiao Xueyu Hu Zhuojing Luo Liu Yang liping tong Di Chen Research Center for Computer-aided Drug Discovery Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenChina Faculty of Pharmaceutical Sciences Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenChina Division of Spine Surgery the First Affiliated Hospital of Guangxi Medical UniversityNanningGuangxiChina Department of Orthopedic Surgery Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA Institute of Orthopedics Xijing Hospitalthe Fourth Military Medical UniversityXi’anChina Department of Spine Surgery Peking University Shenzhen HospitalShenzhenChina Department of Clinical Medicine School of MedicineZhejiang University City CollegeHangzhouZhejiangChina Departments of Physical Medicine&Rehabilitation Perelman School of MedicineUniversity of PennsylvaniaPAUSA School of Medicine Southern University of Science and TechnologyShenzhenChina

Spine degeneration is an aging-related disease,but its molecular mechanisms remain unknown,although elevatedβ-catenin signaling has been reported to be involved in intervertebral disc degeneration.Here,we determined the role ofβ-catenin signaling in spinal degeneration and in the homeostasis of the functional spinal unit(FSU),which includes the intervertebral disc,vertebra and facet joint and is the smallest physiological motion unit of the spine.We showed that pain sensitivity in patients with spinal degeneration is highly correlated withβ-catenin protein levels.We then generated a mouse model of spinal degeneration by transgenic expression of constitutively activeβ-catenin in Col2^(+) cells.We found thatβ-catenin-TCF7 activated the transcription of CCL2,a known critical factor in osteoarthritic pain.Using a lumbar spine instability model,we showed that aβ-catenin inhibitor relieved low back pain.Our study indicates thatβ-catenin plays a critical role in maintaining spine tissue homeostasis,its abnormal upregulation leads to severe spinal degeneration,and its targeting could be an avenue to treat this condition.

关键词： degeneration smallest homeostasis

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Hsa_circ_0007099 and PIP4K2A coexpressed in diffuse large B-cell lymphoma with clinical significance

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Genes & Diseases 2024年第4期11卷 98-101页

作者： Jinghan Wang Xin Ku Qiuling Ma Haikuo Li Sujuan Huang liping Mao Fang Yu Jie Jin Wei Yan Department of Hematology The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310003China Key Laboratory of Hematologic Malignancies Diagnosis and TreatmentHangzhouZhejiang 310003China Zhejiang Provincial Clinical Research Center for Hematologic Diseases HangzhouZhejiang 310003China Cancer Center Zhejiang UniversityHangzhouZhejiang 310003China Shanghai Center for Systems Biomedicine Key Laboratory of Systems Biomedicine(Ministry of Education)Shanghai JiaoTong UniversityShanghai 200240China The Second School of Clinical Medicine Henan University of Chinese MedicineZhengzhouHenan 450046China Department of Pathology The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310003China

Diffuse large B-cell lymphoma(DLBCL)is the most common subtype of B-cell lymphoma in adult patients.Due to the clinical and molecular heterogeneity of DLBCL patients,robust biomarkers in clinical practice are still re... 详细信息

关键词： clinical lymphoma patients

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A programmed surface on polyetheretherketone for sequentially dictating osteoimmunomodulation and bone regeneration to achieve ameliorative osseointegration under osteoporotic conditions

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Bioactive Materials 2022年第8期7卷 364-376页

作者： Yanyan Zheng Ang Gao Jiaxiang Bai Qing Liao Yuzheng Wu Wei Zhang Min Guan liping tong Dechun Geng Xin Zhao Paul K.Chu Huaiyu Wang Center for Human Tissues and Organs Degeneration Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen518055China School of Basic Medical Sciences and Forensic Medicine North Sichuan Medical CollegeNanchong637000China Department of Orthopaedics The First Affiliated Hospital of Soochow UniversitySuzhou215006China Department of Physics Department of Materials Science and EngineeringDepartment of Biomedical EngineeringCity University of Hong KongTat Chee AvenueKowloonHong KongChina Technical Institute of Physics and Chemistry Chinese Academy of SciencesBeijing100190China Department of Biomedical Engineering The Hong Kong Polytechnic UniversityHong KongChina

Polyetheretherketone(PEEK)is a desirable alternative to conventional biomedical metals for orthopedic implants due to the excellent mechanical properties.However,the inherent bioinertness of PEEK contributes to inferior osseointegration of PEEK implants,especially under pathological conditions of osteoporosis.Herein,a programmed surface is designed and fabricated on PEEK to dictate osteoimmunomodulation and bone regeneration sequentially.A degradable hybrid coating consisting of poly(lactide-co-glycolide)and alendronate(ALN)loaded nano-hydroxyapatite is deposited on PEEK and then interleukin-4(IL-4)is grafted onto the outer surface of the hybrid coating with the aid of N_(2) plasma immersion ion implantation and subsequent immersion in IL-4 solution.Dominant release of IL-4 together with ALN and Ca^(2+) during the first few days synergistically mitigates the early acute inflammatory reactions and creates an osteoimmunomodulatory microenvironment that facilitates bone regeneration.Afterwards,slow and sustained delivery of ALN and Ca^(2+) in the following weeks boosts osteogenesis and suppresses osteoclastogenesis simultaneously,consequently ameliorating bone-implant osseointegration even under osteoporotic conditions.By taking into account the different phases in bone repair,this strategy of constructing advanced bone implants with sequential functions provides customizable and clinically viable therapy to osteoporotic patients.

关键词： Polyetheretherketone Surface modification Osteoimmunomodulation Sequential release Osteoporosis Osseointegration

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Endorepellin downregulation promotes angiogenesis after experimental traumatic brain injury

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Neural Regeneration Research 2024年第5期19卷 1092-1097页

作者： Qian Zhang Yao Jing Qiuyuan Gong Lin Cai Ren Wang Dianxu Yang liping Wang Meijie Qu Hao Chen Yaohui Tang Hengli Tian Jun Ding Zhiming Xu Department of Gerontology Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina Department of Neurosurgery Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina Department of Neurology Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina School of Biomedical Engineering and Med-X Research Institute Shanghai Jiao Tong UniversityShanghaiChina Department of Neurology Affiliated Hospital of Qingdao UniversityQingdaoShandong ProvinceChina

Endorepellin plays a key role in the regulation of angiogenesis,but its effects on angiogenesis after traumatic brain injury are unclear.This study explored the effects of endorepellin on angiogenesis and neurobehavioral outcomes after traumatic brain injury in mice.Mice were randomly divided into four groups:sham,controlled cortical impact only,adeno-associated virus(AAV)-green fluorescent protein,and AAV-shEndorepellin-green fluorescent protein groups.In the controlled cortical impact model,the transduction of AAV-shEndorepellin-green fluorescent protein downregulated endorepellin while increasing the number of CD31+/Ki-67+proliferating endothelial cells and the functional microvessel density in mouse brain.These changes resulted in improved neurological function compared with controlled cortical impact mice.Western blotting revealed increased expression of vascular endothelial growth factor and angiopoietin-1 in mice treated with AAV-shEndorepellin-green fluorescent protein.Synchrotron radiation angiography showed that endorepellin downregulation promoted angiogenesis and increased cortical neovascularization,which may further improve neurobehavioral outcomes.Furthermore,an in vitro study showed that downregulation of endorepellin increased tube formation by human umbilical vein endothelial cells compared with a control.Mechanistic analysis found that endorepellin downregulation may mediate angiogenesis by activating vascular endothelial growth factor-and angiopoietin-1-related signaling pathways.

关键词： angiogenesis controlled cortical impact endorepellin neurological function traumatic brain injury

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Current understanding of osteoarthritis pathogenesis and relevant new approaches

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Bone Research 2022年第4期10卷 627-643页

作者： liping tong Huan Yu Xingyun Huang Jie Shen Guozhi Xiao Lin Chen Huaiyu Wang Lianping Xing Di Chen Research Center for Computer-aided Drug Discovery Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518005China Faculty of Pharmaceutical Sciences Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Department of Orthopedic Surgery School of MedicineWashington University in St.LouisSt.LouisMO 63110USA School of Medicine Southern University of Science and TechnologyShenzhen 518055China Department of Wound Repair and Rehabilitation State Key Laboratory of TraumaBurns and Combined InjuryDaping HospitalArmy Medical UniversityChongqing 400042China Research Center for Human Tissues and Organs Degeneration Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Department of Pathology and Laboratory of Medicine Center for Musculoskeletal ResearchUniversity of Rochester Medical CenterRochesterNY 14642USA

Osteoarthritis(OA)is the most common degenerative joint disease that causes painful swelling and permanent damage to the joints in the body.The molecular mechanisms of OA are currently unknown.OA is a heterogeneous disease that affects the entire joint,and multiple tissues are altered during OA development.To better understand the pathological mechanisms of OA,new approaches,methods,and techniques need to be used to understand OA pathogenesis.In this review,we first focus on the epigenetic regulation of OA,with a particular focus on DNA methylation,histone modification,and microRNA regulation,followed by a summary of several key mediators in OA-associated pain.We then introduce several innovative techniques that have been and will continue to be used in the fields of OA and OA-associated pain,such as CRISPR,scRNA sequencing,and lineage tracing.Next,we discuss the timely updates concerning cell death regulation in OA pathology,including pyroptosis,ferroptosis,and autophagy,as well as their individual roles in OA and potential molecular targets in treating OA.Finally,our review highlights new directions on the role of the synovial lymphatic system in OA.An improved understanding of OA pathogenesis will aid in the development of more specific and effective therapeutic interventions for OA.

关键词： pathogenesis swelling concerning

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