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Paeoniflorin,the Main Monomer Component of Paeonia lactiflora,Exhibits Anti-inflammatory Properties in Osteoarthritis Synovial Inflammation

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Chinese Journal of Integrative Medicine 2024年第5期30卷 433-442页

作者： CHEN Pu ZHOU Jun RUAN An-min MA Yu-feng WANG Qing-fu Department of Orthopaedic Surgery Beijing University of Chinese Medicine Third Affiliated HospitalBeijing 100029China Department of Orthopaedic Surgery Guangdong Provincial Hospital of Chinese MedicineGuangzhou 510120China Department of Orthopaedic Surgery Beijing Longfu HospitalBeijing 100010China

Objective:To explore the mechanism of paeoniflorin(PF)on Osteoarthritis(OA)synovial inflammation from network pharmacology to experimental pharmacology.Methods:Targets of OA were constructed by detecting the database of network database platforms(Therapeutic Target database,Drug Bank and Gene Cards),and the targets of PF were constructed by Pub Chem and Herbal Ingredients'Targets database.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis of these co-targeted genes were conducted via Database for Annotation,Visualization,and Integrated Discovery(DAVID)database,and protein-protein interaction(PPI)networks were conducted via the search tool for the retrieval of interacting genes(STRING)database.Cell counting kit-8(CCK-8)assay was performed to assess the potential toxicity of PF on human OA fibroblast-like synoviocytes(FLS),quantitative real-time polymerase chain reaction(q PCR),enzyme-linked immunosorbent assay(ELISA)and Western blot were used to verify the potential mechanism of PF in synovial inflammation.Results:Twenty-six co-targeted genes were identified.GO enrichment results showed that these co-targeted genes were most likely localized in the cytoplasm,and the biological processes mainly involved'cellular response to hypoxia''lipopolysaccharide(LPS)-mediated signaling pathway'and'positive regulation of gene expression'.KEGG pathway analysis indicated that these co-targeted genes may function through pathways associated with'hypoxia-inducible factor-1(HIF-1)signaling pathway'and'tumornecrosis factor(TNF)signaling pathway'.The PPI network showed that the top 3 hub genes were TP53,TNF,and CASP3.Molecular docking results showed that PF was well docking with TNF.CCK-8 showed no potential toxicity of 10,20 and 50μmol/L PF on human OA FLS.And PF significantly decreased the expression levels of interleukin-1β,interleukin-6,TNF-αmatrix metalloproteinase 13(MMP13),and a disintegrin and metalloproteinase with thrombospondin motifs 5(ADAMTS5)and TNF-αin LPS-induced OA FLS.Conclusion:PF exhibited

关键词： paeoniflorin Osteoarthritis synovial inflammation tumor necrosis factor-α network pharmacology Paeonia lactiflora

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Pathological progression of Osteoarthritis:a perspective on subchondral bone

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Frontiers of Medicine 2024年第2期18卷 237-257页

作者： Xuefei Li Wenhua Chen Dan Liu Pinghua Chen Shiyun Wang Fangfang Li Qian Chen Shunyi Lv Fangyu Li Chen Chen Suxia Guo Weina Yuan Pan Li Zhijun Hu Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine Shanghai200032China Research and Development Center of Chinese Medicine Resources and Biotechnology Shanghai University of Traditional Chinese MedicineShanghai201203China

Osteoarthritis(OA)is a degenerative bone disease associated with aging.The rising global aging population has led to a surge in OA cases,thereby imposing a significant socioeconomic burden.Researchers have been keenly investigating the mechanisms underlying OA.Previous studies have suggested that the disease starts with synovial inflammation and hyperplasia,advancing toward cartilage degradation.Ultimately,subchondral-bone collapse,sclerosis,and osteophyte formation occur.This progression is deemed as“top to bottom.”However,recent research is challenging this perspective by indicating that initial changes occur in subchondral bone,precipitating cartilage breakdown.In this review,we elucidate the epidemiology of OA and present an in-depth overview of the subchondral bone’s physiological state,functions,and the varied pathological shifts during OA progression.We also introduce the role of multifunctional signal pathways(including osteoprotegerin(OPG)/receptor activator of nuclear factor-kappa B ligand(RANKL)/receptor activator of nuclear factor-kappa B(RANK),and chemokine(CXC motif)ligand 12(CXCL12)/CXC motif chemokine receptor 4(CXCR4))in the pathology of subchondral bone and their role in the“bottom-up”progression of OA.Using vivid pattern maps and clinical images,this review highlights the crucial role of subchondral bone in driving OA progression,illuminating its interplay with the condition.

关键词： Osteoarthritis subchondral bone OPG/RANKL/RANK CXCL12/CXCR4

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Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates Osteoarthritis

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Bone Research 2024年第1期12卷 215-226页

作者： Yuhang Liu Ruihan Hao Jia Lv Jie Yuan Xuelei Wang Churong Xu Ding Ma Zhouyi Duan Bingjun Zhang Liming Dai Yiyun Cheng Wei Lu Xiaoling Zhang Department of Orthopedic Surgery Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine(SJTUSM)Shanghai 200092China National Facility for Translational Medicine Shanghai 200240China Shanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory BiologySchool of Life SciencesEast China Normal UniversityShanghai 200241China Department of Orthopaedic Surgery The Second Hospital of Shanxi Medical UniversityTaiyuan 030001China CAS Key Laboratory of Tissue Microenvironment and Tumor Shanghai Institute of Nutrition and HealthChinese Academy of SciencesShanghai 200031China School of Medicine Shanghai UniversityShanghai 200444China

Osteoarthritis(OA)is a common degenerative disease worldwide and new therapeutics that target inflammation and the crosstalk between immunocytes and chondrocytes are being developed to prevent and treat OA.These attempts involve repolarizing pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype in synovium.In this study,we found that phosphoglycerate mutase 5(PGAM5)significantly increased in macrophages in OA synovium compared to controls based on histology of human samples and single-cell RNA sequencing results of mice models.To address the role of PGAM5 in macrophages in OA,we found conditional knockout of PGAM5 in macrophages greatly alleviated OA symptoms and promoted anabolic metabolism of chondrocytes in vitro and in vivo.Mechanistically,we found that PGAM5 enhanced M1 polarization via AKT-mTOR/p38/ERK pathways,whereas inhibited M2 polarization via STAT6-PPARγpathway in murine bone marrow-derived macrophages.Furthermore,we found that PGAM5 directly dephosphorylated Dishevelled Segment Polarity Protein 2(DVL2)which resulted in the inhibition ofβ-catenin and repolarization of M2 macrophages into M1 macrophages.Conditional knockout of both PGAM5 andβ-catenin in macrophages significantly exacerbated Osteoarthritis compared to PGAM5-deficient mice.Motivated by these findings,we successfully designed mannose modified fluoropolymers combined with siPGAM5 to inhibit PGAM5 specifically in synovial macrophages via intra-articular injection,which possessed desired targeting abilities of synovial macrophages and greatly attenuated murine Osteoarthritis.Collectively,these findings defined a key role for PGAM5 in orchestrating macrophage polarization and provides insights into novel macrophage-targeted strategy for treating OA.

关键词： Osteoarthritis metabolism inhibited

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Efficacy and safety of extracorporeal shock wave therapy combined with sodium hyaluronate in treatment of knee Osteoarthritis:a systematic review and Meta-analysis

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Journal of Traditional Chinese Medicine 2024年第2期44卷 243-250页

作者： ZHOU Mingwang DONG Zhuanli WEI Changhao FENG Lufang WANG Xiaoping LIU Haiping JI Xing YANG Kehu LI Shenghua Department of Orthopaedics Gansu Provincial Hospital of Traditional Chinese MedicineLanzhou 730050China Department of Quality Management Lanzhou Petrochemical General HospitalLanzhou 730050China Department of Orthopaedics Lanzhou Petrochemical General HospitalLanzhou 730050China Evidence-Based Social Science Research Center School of Public HealthLanzhou UniversityLanzhou730000China Evidence-Based Medicine Center School of Basic Medical SciencesLanzhou UniversityLanzhou 730000China Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province Lanzhou 730000China Center for Translational Medicine Gansu Provincial Hospital of Traditional Chinese MedicineLanzhou 730050China Department of Orthopaedics Gansu Provincial Hospital of Traditional Chinese MedicineLanzhou 730000China

OBJECTIVE:To assess the efficacy and safety of extracorporeal shockwave therapy(ESWT)combined with sodium hyaluronate(HA)for the treatment of knee Osteoarthritis(KOA).METHODS:PubM ed,Embase,the Cochrane Library,Web of Science,China National Knowledge Infrastructure,Wanfang database,China Science and Technology Journal Database,and SinoMed were searched from inception to July 2020.The quality of the randomized controlled trials was evaluated independently by two reviewers according to the criteria in the Cochrane Collaboration for Systematic Reviews.The identified articles were then screened individually using EndnoteX9 for eligibility in this Meta-analysis.The heterogeneity among the articles was evaluated using I2.RESULTS:A total of 17 studies,comprising 2000 individuals,were included in this Meta-analysis.The results showed that a significant improvement was observed in knee pain and function based on the clinical efficacy of ESWT combined with HA.Statistical analysis of clinical efficacy showed that[relative risk(RR)=1.21,95%confidence interval(CI)(1.12,1.30),POsteoarthritis index statistical analysis showed that[SMD=-1.57,95%CI(-2.52,-0.61),P<0.01].Lysholm score statistical analysis showed that[SMD=1.71,95%CI(0.98,2.44),P<0.01].In addition,only minor side effects,such as redness and swelling of the skin,were observed.CONCLUSIONS:Medium to low quality evidence showed that ESWT combined with HA offers an inexpensive,welltolerated,safe,and effective method to improve pain and functionality in patients with KOA.However,tightly controlled,randomized,large multicenter trials are warranted to validate the current findings.

关键词： Osteoarthritis knee randomized controlled trial extracorporeal shockwave therapy hyaluronic acid Meta-analysis

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Osteoarthritis versus psoriasis arthritis: Physiopathology, cellular signaling, and therapeutic strategies

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Genes & Diseases 2024年第3期11卷 232-247页

作者： Salma Nassor Juma Junguang Liao Yuping Huang Rexhina Vlashi Qingwan Wang Bocong Wu Dan Wang Mengrui Wu Guiqian Chen College of Life Science and Medicine Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and BiomedicineZhejiang Sci-Tech UniversityHangzhouZhejiang 310018China Department of Cell and Developmental Biology College of Life SciencesZhejiang UniversityHangzhouZhejiang 310058China

Osteoarthritis and psoriasis arthritis are two degenerative forms of arthritis that share similar yet also different manifestations at the histological,cellular,and clinical levels.Rheumatologists have marked them as two entirely distinct arthropathies.Given recent dis-coveries in disease initiation and progression,potential mechanisms,cellular signaling path-ways,and ongoing clinical therapeutics,there are now more opportunities for discovering Osteoarthritis drugs.This review summarized the Osteoarthritis and psoriasis arthritis signaling pathways,crosstalk between BMP,WNT,TGF-β,VEGF,TLR,and FGF signaling pathways,bio-markers,and anatomical pathologies.Through bench research,we demonstrated that regen-erative medicine is a promising alternative for treating Osteoarthritis by highlighting significant scientific discoveries on entheses,multiple signaling blockers,and novel molecules such as immunoglobulin new antigen receptors targeted for potential drug evaluation.Furthermore,we offered valuable therapeutic approaches with a multidisciplinary strategy to treat patients with Osteoarthritis or psoriasis arthritis in the coming future in the clinic.

关键词： Newantigen receptor Osteoarthritis Physiopathology Psoriasisarthritis Signaling pathway

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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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The miR-21-5p enriched in the apoptotic bodies of M2 macrophage-derived extracellular vesicles alleviates Osteoarthritis by changing macrophage phenotype

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Genes & Diseases 2023年第3期10卷 1114-1129页

作者： Leilei Qin Jianye Yang Xudong Su Xilan li Yiting Lei Lili Dong Hong Chen Cheng Chen Chen Zhao Huan Zhang Jun Deng Ning Hu Wei Huang Department of Orthopaedics The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Orthopedic Laboratory of Chongqing Medical University The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Institute of Burn Research Southwest HospitalState Key Lab of TraumaBurn and Combined InjuryArmy Medical UniversityChongqing 400038China

Macrophages (Mφs) play a crucial role in the pathological progression of Osteoarthritis (OA) by regulating inflammation and tissue repair. Decreasing pro-inflammatory M1-Mφs and increasing anti-inflammatory M2-Mφs can alleviate OA-related inflammation and promote cartilage repair. Apoptosis is a natural process associated with tissue repair. A large number of apoptotic bodies (ABs), a type of extracellular vesicle, are produced during apoptosis, and this is associated with a reduction in inflammation. However, the functions of apoptotic bodies remain largely unknown. In this study, we investigated the role of M2-Mφs-derived apoptotic bodies (M2-ABs) in regulating the M1/M2 balance of macrophages in a mouse model of OA. Our data show that M2-ABs can be targeted for uptake by M1-Mφs, and this reprograms M1-to-M2 phenotypes within 24 h. The M2-ABs significantly ameliorated the severity of OA, alleviated the M1-mediated pro-inflammatory environment, and inhibited chondrocyte apoptosis in mice. RNA-seq revealed that M2-ABs were enriched with miR-21–5p, a microRNA that is negatively correlated with articular cartilage degeneration. Inhibiting the function of miR-21–5p in M1-Mφs significantly reduced M2-ABs-guided M1-to-M2 reprogramming following in vitro cell transfection. Together, these results suggest that M2-derived apoptotic bodies can prevent articular cartilage damage and improve gait abnormalities in OA mice by reversing the inflammatory response caused by M1 macrophages. The mechanism underlying these findings may be related to miR-21-5p-regulated inhibition of inflammatory factors. The application of M2-ABs may represent a novel cell therapy, and could provide a valuable strategy for the treatment of OA and/or chronic inflammation.

关键词： Apoptotic body Extracellular vesicles Macrophage phenotype switch Micr oRNA-21 Osteoarthritis

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Beneficial Effects and Potential Mechanisms of Tai Chi on Lower Limb Osteoarthritis:A Biopsychosocial Perspective

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Chinese Journal of Integrative Medicine 2023年第4期29卷 368-376页

作者： ZHUANG Shu-zhao CHEN Pei-jie HAN Jia XIAO Wei-hua Shanghai Frontiers Science Research Base of Exercise and Metabolic Health Shanghai University of SportShanghai 200438China

Lower limb Osteoarthritis(OA)is a chronic,multifactorial disease characterized by impaired physical function,chronic pain,compromised psychological health and decreased social functioning.Chronic inflammation plays a critical role in the pathophysiology of OA.Tai Chi is a type of classical mind-body exercise derived from ancient Chinese martial arts.Evidence supports that Tai Chi has significant benefits for relieving lower limb OA symptoms.Using a biopsychosocial framework,this review aims to elucidate the beneficial effects of Tai Chi in lower limb OA and disentangle its potential mechanisms from the perspective of biology,psychology,and social factors.Complex biomechanical,biochemical,neurological,psychological,and social mechanisms,including strengthening of muscles,proprioception improvement,joint mechanical stress reduction,change of brain activation and sensitization,attenuation of inflammation,emotion modulation and social support,are discussed.

关键词： Tai Chi Osteoarthritis mechanism biopsychosocialmodel

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GPRC5B protects Osteoarthritis by regulation of autophagy signaling

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药学学报:英文版 2023年第7期13卷 2976-2989页

作者： Liang He Ziwei Xu Xin Niu Rong Li Fanhua Wang Yu You Jingduo Gao Lei Zhao Karan M.Shah Jian Fan Mingyao Liu Jian Luo Yangzhi Rehabilitation Hospital(Shanghai Sunshine Rehabilitation Center) Tongji University School of MedicineShanghai 201613China Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai 200241China Department of Oncology and Metabolism the Medical Schoolthe University of SheffieldSheffield S102TNUK Department of Orthopedics Tongji HospitalTongji University School of MedicineShanghai 200092China

Osteoarthritis(OA)is one of the most common chronic diseases in the world.However,current treatment modalities mainly relieve pain and inhibit cartilage degradation,but do not promote cartilage regeneration.In this study,we show that G protein-coupled receptor class C group 5 member B(GPRC5B),an orphan G-protein-couple receptor,not only inhibits cartilage degradation,but also increases cartilage regeneration and thereby is protective against OA.We observed that Gprc5b deficient chondrocytes had an upregulation of cartilage catabolic gene expression,along with downregulation of anabolic genes in vitro.Furthermore,mice deficient in Gprc5b displayed a more severe OA phenotype in the destabilization of the medial meniscus(DMM)induced OA mouse model,with upregulation of cartilage catabolic factors and downregulation of anabolic factors,consistent with our in vitro findings.Overexpression of Gprc5b by lentiviral vectors alleviated the cartilage degeneration in DMM-induced OA mouse model by inhibiting cartilage degradation and promoting regeneration.We also assessed the molecular mechanisms downstream of Gprc5b that may mediate these observed effects and identify the role of protein kinase B(AKT)-mammalian target of rapamycin(m TOR)-autophagy signaling pathway.Thus,we demonstrate an integral role of GPRC5B in OA pathogenesis,and activation of GPRC5B has the potential in preventing the progression of OA.

关键词： Osteoarthritis GPRC5B Cartilage Chondrocyte Cartilage anabolism and catabolism Cartilage regeneration Autophagy Drug target

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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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