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Kindlin-2 inhibits Nlrp3 inflammasome activation in nucleus pulposus to maintain homeostasis of the intervertebral disc

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Bone Research 2022年第1期10卷 165-177页

作者： Sheng Chen xiaohao wu Yumei Lai Di Chen Xiaochun Bai Sheng Liu Yongchao wu Mingjue Chen Yuxiao Lai Huiling Cao Zengwu Shao Guozhi Xiao Department of Orthopaedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China Department of Biochemistry School of MedicineSouthern University of Science and TechnologyGuangdong Provincial Key Laboratory of Cell Microenvironment and Disease ResearchShenzhen Key Laboratory of Cell MicroenvironmentShenzhen 518055China Department of Orthopedic Surgery Rush University Medical CenterChicagoIL 60612USA Research Center for Human Tissues and Organs Degeneration Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Department of Cell Biology School of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510515China Centre for Translational Medicine Research and Development Institute of Biomedical and Health EngineeringShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China

Intervertebral disc(IVD) degeneration(IVDD) is the main cause of low back pain with major social and economic burdens;however, its underlying molecular mechanisms remain poorly defined. Here we show that the focal adhesion protein Kindlin-2 is highly expressed in the nucleus pulposus(NP), but not in the anulus fibrosus and the cartilaginous endplates, in the IVD tissues. Expression of Kindlin-2 is drastically decreased in NP cells in aged mice and severe IVDD patients. Inducible deletion of Kindlin-2 in NP cells in adult mice causes spontaneous and striking IVDD-like phenotypes in lumbar IVDs and largely accelerates progression of coccygeal IVDD in the presence of abnormal mechanical stress. Kindlin-2 loss activates Nlrp3 inflammasome and stimulates expression of IL-1β in NP cells, which in turn downregulates Kindlin-2. This vicious cycle promotes extracellular matrix(ECM) catabolism and NP cell apoptosis. Furthermore, abnormal mechanical stress reduces expression of Kindlin-2, which exacerbates Nlrp3 inflammasome activation, cell apoptosis, and ECM catabolism in NP cells caused by Kindlin-2 deficiency. In vivo blocking Nlrp3 inflammasome activation prevents IVDD progression induced by Kindlin-2 loss and abnormal mechanical stress. Of translational significance, adeno-associated virus-mediated overexpression of Kindlin-2 inhibits ECM catabolism and cell apoptosis in primary human NP cells in vitro and alleviates coccygeal IVDD progression caused by mechanical stress in rat. Collectively, we establish critical roles of Kindlin-2 in inhibiting Nlrp3 inflammasome activation and maintaining integrity of the IVD homeostasis and define a novel target for the prevention and treatment of IVDD.

关键词： Kindlin homeostasis prevention

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Osteoarthritis:pathogenic signaling pathways and therapeutic targets

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Signal Transduction and Targeted Therapy 2023年第3期8卷 932-962页

作者： Qing Yao xiaohao wu Chu Tao Weiyuan Gong Mingjue Chen Minghao Qu Yiming Zhong Tailin He Sheng Chen Guozhi Xiao Department of Biochemistry School of MedicineShenzhen Key Laboratory of Cell MicroenvironmentGuangdong Provincial Key Laboratory of Cell Microenvironment and Disease ResearchSouthern University of Science and TechnologyShenzhen 518055China Department of Orthopaedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China

Osteoarthritis(OA)is a chronic degenerative joint disorder that leads to disability and affects more than 500 million population *** was believed to be caused by the wearing and tearing of articular cartilage,but it is now more commonly referred to as a chronic whole-joint disorder that is initiated with biochemical and cellular alterations in the synovial joint tissues,which leads to the histological and structural changes of the joint and ends up with the whole tissue ***,there is no cure for OA,partly due to a lack of comprehensive understanding of the pathological mechanism of the initiation and progression of the ***,a better understanding of pathological signaling pathways and key molecules involved in OA pathogenesis is crucial for therapeutic target design and drug *** this review,we first summarize the epidemiology of OA,including its prevalence,incidence and burdens,and OA risk *** then focus on the roles and regulation of the pathological signaling pathways,such as Wnt/β-catenin,NF-κB,focal adhesion,HIFs,TGFβ/ΒΜP and FGF signaling pathways,and key regulators AMPK,mTOR,and RUNX2 in the onset and development of *** addition,the roles of factors associated with OA,including MMPs,ADAMTS/ADAMs,and PRG4,are discussed in ***,we provide updates on the current clinical therapies and clinical trials of biological treatments and drugs for *** advances in basic knowledge of articular cartilage biology and OA pathogenesis will have a significant impact and translational value in developing OA therapeutic strategies.

关键词： therapeutic Osteoarthritis epidemiology

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Kindlin-2 loss in condylar chondrocytes causes spontaneous osteoarthritic lesions in the temporomandibular joint in mice

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International Journal of Oral Science 2022年第3期14卷 371-380页

作者： Yumei Lai Wei Zheng Minghao Qu Christopher C.Xiao Sheng Chen Qing Yao Weiyuan Gong Chu Tao Qinnan Yan Peijun Zhang xiaohao wu Guozhi Xiao Department of Orthopedic Surgery Rush University Medical CenterChicagoILUSA Department of Orthopaedic Center Xinjiang Production and Construction Corps HospitalUrumqiChina Department of Biochemistry School of MedicineSouthern University of Science and TechnologyGuangdong Provincial Key Laboratory of Cell Microenvironment and Disease ResearchShenzhen Key Laboratory of Cell MicroenvironmentShenzhenChina Department of Orthopedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

The progressive destruction of condylar cartilage is a hallmark of the temporomandibular joint(TMJ) osteoarthritis(OA);however, its mechanism is incompletely understood. Here, we show that Kindlin-2, a key focal adhesion protein, is strongly detected in cells of mandibular condylar cartilage in mice. We find that genetic ablation of Kindlin-2 in aggrecan-expressing condylar chondrocytes induces multiple spontaneous osteoarthritic lesions, including progressive cartilage loss and deformation, surface fissures, and ectopic cartilage and bone formation in TMJ. Kindlin-2 loss significantly downregulates the expression of aggrecan, Col2a1 and Proteoglycan 4(Prg4), all anabolic extracellular matrix proteins, and promotes catabolic metabolism in TMJ cartilage by inducing expression of Runx2and Mmp13 in condylar chondrocytes. Kindlin-2 loss decreases TMJ chondrocyte proliferation in condylar cartilages. Furthermore,Kindlin-2 loss promotes the release of cytochrome c as well as caspase 3 activation, and accelerates chondrocyte apoptosis in vitro and TMJ. Collectively, these findings reveal a crucial role of Kindlin-2 in condylar chondrocytes to maintain TMJ homeostasis.

关键词： Kindlin-2 loss in condylar chondrocytes causes spontaneous osteoarthritic lesions in the temporomandibular joint in mice TMJ

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Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice

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Signal Transduction and Targeted Therapy 2021年第1期6卷 131-143页

作者： Xuekun Fu Bo Zhou Qinnan Yan Chu Tao Lei Qin xiaohao wu Sixiong Lin Sheng Chen Yumei Lai Xuenong Zou Zengwu Shao Meiqing Wang Di Chen Wenfei Jin Youqiang Song Huiling Cao Ge Zhang Guozhi Xiao School of Medicine Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Researchand Shenzhen Key Laboratory of Cell MicroenvironmentSouthern University of Science and Technology1088 Xue Yuan Road518055 ShenzhenGuangdongChina Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases School of Chinese MedicineHong Kong Baptist University999077 Hong KongSARChina Department of Biology Southern University of Science and Technology518055 ShenzhenChina School of Biomedical Sciences University of Hong Kong21 Sassoon RoadHong KongChina Department of Spine Surgery Orthopedic Research InstituteThe First Affiliated Hospital of Sun Yat-sen UniversityGuangdong Provincial Key Laboratory of Orthopedics and Traumatology510080 GuangzhouChina Department of Orthopedics Union HospitalTongji Medical CollegeHuazhong University of Science and Technology430022 WuhanChina Department of Orthopedic Surgery Rush University Medical CenterChicagoIL 60612USA State Key Laboratory of Military Stomatology National Clinical Research Center for Oral DiseasesShanxi International Joint Research Center for Oral DiseasesDepartment of Oral Anatomy and Physiology and TMDSchool of Stomatologythe Fourth Military Medical University145 Changle West RoadXi’anChina Research Center for Human Tissues and Organs Degeneration Shenzhen Institutes of Advanced TechnologyChinese Academy of Sciences518055 ShenzhenChina

In vertebrates,the type 1 parathyroid hormone receptor(PTH1R)is a critical regulator of skeletal development and homeostasis;however,how it is modulated is incompletely *** we report that deleting Kindlin-2 in osteoblastic cells using the mouse 10-kb Dmp1-Cre largely neutralizes the intermittent PTH-stimulated increasing of bone volume fraction and bone mineral density by impairing both osteoblast and osteoclast formation in murine adult ***-cell profiling reveals that Kindlin-2 loss increases the proportion of osteoblasts,but not mesenchymal stem cells,chondrocytes and fibroblasts,in non-hematopoietic bone marrow cells,with concomitant depletion of osteoblasts on the bone surfaces,especially those stimulated by ***,haploinsufficiency of Kindlin-2 and Pth1r genes,but not that of either gene,in mice significantly decreases basal and,to a larger extent,PTH-stimulated bone mass,supporting the notion that both factors function in the same genetic ***,Kindlin-2 interacts with the C-terminal cytoplasmic domain of PTH1R via aa 474–475 and Gsα.Kindlin-2 loss suppresses PTH induction of cAMP production and CREB phosphorylation in cultured osteoblasts and in ***,PTH promotes Kindlin-2 expression in vitro and in vivo,thus creating a positive feedback regulatory ***,estrogen deficiency induced by ovariectomy drastically decreases expression of Kindlin-2 protein in osteocytes embedded in the bone matrix and Kindlin-2 loss essentially abolishes the PTH anabolic activity in bone in ovariectomized ***,we demonstrate that Kindlin-2 functions as an intrinsic component of the PTH1R signaling pathway in osteoblastic cells to regulate bone mass accrual and homeostasis.

关键词： homeostasis Kindlin skeletal

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Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis

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Bone Research 2024年第2期12卷 421-437页

作者： Hongzhen Chen Xuekun Fu xiaohao wu Junyi Zhao Fang Qiu Zhenghong Wang Zhuqian Wang Xinxin Chen Duoli Xie Jie Huang Junyu Fan Xu Yang Yi Song Jie Li Dongyi He Guozhi Xiao Aiping Lu Chao Liang Department of Systems Biology School of Life SciencesSouthern University of Science and TechnologyGuangdong Provincial Key Laboratory of Cell Microenvironment and Disease ResearchShenzhen Key Laboratory of Cell MicroenvironmentShenzhen 518055China Institute of Integrated Bioinfomedicine and Translational Science(IBTS) School of Chinese MedicineHong Kong Baptist UniversityHong Kong SAR 999077China Department of Biochemistry School of MedicineSouthern University of Science and TechnologyGuangdong Provincial Key Laboratory of Cell Microenvironment and Disease ResearchShenzhen Key Laboratory of Cell MicroenvironmentShenzhen 518055China Division of Immunology and Rheumatology Stanford UniversityStanfordCA 94305USA VA Palo Alto Health Care System Palo AltoCA 94304USA Institute of Plant and Food Science Department of BiologySouthern University of Science and TechnologyShenzhen 518055China Department of Rheumatology Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghai University of Traditional Chinese MedicineShanghaiChina Department of Computational Biology St.Jude Children’s Research HospitalMemphisTNUSA Department of Laboratory Medicine Peking University Shenzhen HospitalShenzhenChina Guangdong-Hong Kong-Macao Joint Lab on Chinese Medicine and Immune Disease Research Guangzhou 510006China Shanghai University of Traditional Chinese Medicine Shanghai 200032China State Key Laboratory of Proteomics National Center for Protein Sciences(Beijing)Beijing Institute of Lifeomics100850 BeijingChina

Rheumatoid arthritis(RA)is an autoimmune *** studies hold an opinion that gut microbiota is environmentally acquired and associated with RA ***,accumulating evidence demonstrates that genetics also shape the gut *** is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis(CIA),while the others are resistant to ***,we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice.C57BL/6J mice and healthy human individuals have enriched *** than DBA/1J mice and RA *** of *** prevents CIA in DBA/1J *** identify that *** mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of ***-like synoviocytes(FLSs)in RA are activated to undergo tumor-like *** disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1,resulting in reduced FOXK1 stability,blocked interferon signaling and deactivation of *** treat CIA mice with propionate and show that propionate attenuates ***,a combination of propionate with anti-TNF etanercept synergistically relieves *** results suggest that *** or propionate could be an alternative or complementary approach to the current therapies.

关键词： HDAC3 cytes interferon

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创业者的受教育程度与就业乘数效应——基于北京市海淀区青年创业者调查的实证研究

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教育研究 2017年第1期38卷 39-51页

作者：丁小浩伍银多北京大学教育经济研究所/国家发展研究院北京大学教育学院

2015年对北京市海淀区青年创业者的调查发现,自主创业者的受教育程度与创业就业乘数呈现正向的相关性,自主创业者受教育程度越高,企业规模可能越大,拉动就业效应更明显;自主创业者的受教育程度对于就业乘数的作用,在不同行业上差别较为... 详细信息

2015年对北京市海淀区青年创业者的调查发现,自主创业者的受教育程度与创业就业乘数呈现正向的相关性,自主创业者受教育程度越高,企业规模可能越大,拉动就业效应更明显;自主创业者的受教育程度对于就业乘数的作用,在不同行业上差别较为明显,尤以在农、林、牧、渔业中的作用最为积极,但在不同行业中创业者受教育程度作用的异质性表现得非常明显;没有充分证据说明,在对从业人员智力需求较高的行业里,创业者的受教育程度对就业乘数起着更为积极的作用,农、林、牧、渔业和金融业都是比较明显的反例。扩大自主创业的就业乘数效应,提高创业政策科学性,有必要加强对创业活动的引导、完善高校创业教育体系,并对创业效率进行更细致的成本—效益评估。

关键词：自主创业拉动就业乘数效应受教育程度

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地下连续墙施工中的GXJ接头应用研究

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建筑施工 2018年第4期40卷 463-464,467页

作者：吴晓皓上海公路桥梁(集团)有限公司上海200433

上海轨道交通13号线张江路站基坑工程的地下连续墙大量采用了新型柔性GXJ接头。以此为背景,介绍了GXJ接头的构造及施工方案。从实施效果看,GXJ接头可以在地下连续墙接缝处增加橡胶止水带,大大增强了接缝的抗渗能力。同时,该接头还可避... 详细信息

上海轨道交通13号线张江路站基坑工程的地下连续墙大量采用了新型柔性GXJ接头。以此为背景,介绍了GXJ接头的构造及施工方案。从实施效果看,GXJ接头可以在地下连续墙接缝处增加橡胶止水带,大大增强了接缝的抗渗能力。同时,该接头还可避免混凝土绕流问题,简化了施工工艺,不仅继承了锁口管接头施工方便、价格低廉的特色,而且汲取了十字钢板、H型钢较强防渗能力的优点。

关键词：地下连续墙 GXJ接头橡胶止水带防渗免绕流

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基于语义位置和区域划分的兴趣点推荐模型

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计算机应用研究 2020年第2期37卷 375-380页

作者：刘辉万程峰吴晓浩重庆邮电大学通信与信息工程学院重庆400065 重庆邮电大学通信新技术应用研究中心重庆400065 重庆信科设计有限公司重庆401121

针对现有的位置社交网络研究工作对兴趣点相关的用户语义位置信息挖掘不够充分,且大多推荐算法忽略了兴趣点所在区域对推荐结果的影响,提出了一种新型兴趣点推荐模型(USTTGD)。首先采用分割时间的潜在狄利克雷分配主题模型(latent Diric... 详细信息

针对现有的位置社交网络研究工作对兴趣点相关的用户语义位置信息挖掘不够充分,且大多推荐算法忽略了兴趣点所在区域对推荐结果的影响,提出了一种新型兴趣点推荐模型(USTTGD)。首先采用分割时间的潜在狄利克雷分配主题模型(latent Dirichlet allocation,LDA),基于签到记录中的语义位置信息挖掘时间主题下的用户时间偏好,然后将兴趣点所处区域划分为网格,以评估区域影响;接着应用边缘加权的个性化PageRank(edge-weighted personalized PageRank,EwPPR)来建模兴趣点之间的连续过渡;最后将用户时间偏好、区域偏好和连续过渡偏好融合为一个统一的推荐框架。通过在真实数据集上实验验证,与其他传统推荐模型相比,USTTGD模型在准确率和召回率上有了显著的提升。

关键词：位置社交网络语义位置兴趣点推荐时间主题区域影响

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新媒体时代高校学生基层党组织建设探究

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新闻研究导刊 2023年第23期14卷 176-178页

作者：吴小昊山西通用航空职业技术学院山西大同037304

学生基层党组织是培养学生党员的重要平台,通过组织各种形式的活动可以引导大学生树立正确的世界观、人生观和价值观,同时提升学生的思想政治素养。随着经济社会发展,大众对党员的要求也有所提升,当代学生党员不仅要具备社会责任感和服... 详细信息

学生基层党组织是培养学生党员的重要平台,通过组织各种形式的活动可以引导大学生树立正确的世界观、人生观和价值观,同时提升学生的思想政治素养。随着经济社会发展,大众对党员的要求也有所提升,当代学生党员不仅要具备社会责任感和服务意识,还要具备组织能力和领导才能。因此高校不断优化学生基层党组织建设,为学生搭建更广阔的平台,促使学生在学术、科技、文化、艺术等方面综合发展。当下新媒体已经成为高校学生获取信息、交流思想的重要渠道,对高校学生基层党组织建设而言,新媒体是一把“双刃剑”,虽然能为党组织建设工作提供便利,但同时也会因信息过载而给学生思想带来负面冲击。基于此,文章以新媒体时代高校学生基层党组织建设为研究对象,结合文献资料和笔者工作经验阐述新媒体对高校学生基层党组织建设产生的影响,分析新媒体时代高校学生基层党组织建设存在的问题,并提出新媒体时代加强高校学生基层党组织建设的措施。研究发现,目前最大的难题之一是如何更好地管控新媒体信息,提升大学生对不同信息的辨别能力,避免学生思想受不良信息侵害。

关键词：新媒体高校基层党组织影响问题措施

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基于综合信任的社会化混合推荐算法

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计算机应用研究 2019年第12期36卷 3610-3613页

作者：杨丰瑞吴晓浩万程峰重庆邮电大学通信新技术应用研究中心重庆400065 重庆重邮信科(集团)股份有限公司重庆401121

推荐系统是处理信息过载问题的重要手段,现有的基于信任网络推荐算法没有充分挖掘用户信任关系信息,影响推荐效果。提出了综合评估信任(CETrust)的模型,该模型综合考虑了用户间的直接信任和间接信任等因素。结合推荐项目的特征属性信息... 详细信息

推荐系统是处理信息过载问题的重要手段,现有的基于信任网络推荐算法没有充分挖掘用户信任关系信息,影响推荐效果。提出了综合评估信任(CETrust)的模型,该模型综合考虑了用户间的直接信任和间接信任等因素。结合推荐项目的特征属性信息,集成到概率矩阵的因式分解模型中推荐。实验表明,新提出的推荐算法(H-CETrust)推荐精度高于现有推荐算法。

关键词：推荐系统信任网络信任评估项目特征概率矩阵

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