Fibrosis, inflammation, and osteophyte formation in post-traumatic osteoarthritis
创伤后骨关节炎中的纤维化、炎症和骨赘形成
基本信息
- 批准号:10570315
- 负责人:
- 金额:$ 10.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAccelerationActinsAffectAgonistArthritisAutomobile DrivingBindingBioinformaticsBiological AssayBiologyBone GrowthBone SpurCartilageCell NucleusCell Surface ReceptorsCellsCharacteristicsChondrocytesChronicClinical ResearchComplexCoupledDataDegenerative polyarthritisDevelopmentDiseaseFibroblastsFibrosisG-Protein-Coupled ReceptorsGoalsHealthHumanHypertrophyImmuneIn VitroInflammationInflammatoryInjectionsInjuryInterleukin-6JointsKineticsKneeKnockout MiceKnowledge acquisitionLabelLeucine-Rich RepeatLinkMacrophageMacrophage ActivationMediatingMentorshipMolecularMolecular BiologyMolecular ImmunologyMultimodal ImagingMusMusculoskeletalMyofibroblastOsteoblastsOsteogenesisOutcomePainPathogenesisPathogenicityPathologicPathologyPatient-Focused OutcomesPhasePopulationPositioning AttributeProcessProteinsProteoglycanReporterReporter GenesResearchRoleScienceSecondary toSeveritiesSignal PathwaySignal TransductionSmooth MuscleSynovial CellSynovial FluidSynovial MembraneSynovitisTechnical ExpertiseTestingTissuesTrainingTransgenic OrganismsTraumatic ArthropathyVocational GuidanceWorkarthropathiesarticular cartilagebeta cateninbonecareercartilage degradationcell typecytokinedisabilityeffective therapyimprovedinducible Creinjuredinsightjoint functionjoint injurymineralizationmultiple omicsneutralizing antibodynovelosteochondral tissueosteogenicpain sensitivitypharmacologicpreclinical studyprogenitorreceptorsingle nucleus RNA-sequencingsingle-cell RNA sequencingskill acquisitionskillstranscriptome sequencing
项目摘要
Post-traumatic osteoarthritis (PTOA) is a degenerative joint disease that arises after injury and affects millions
worldwide. There are currently no disease-modifying treatments. PTOA is a complex, multi-tissue joint disease
characterized by pain, cartilage degradation, synovial inflammation and fibrosis, and formation of ectopic bone
growths called osteophytes. The inherent complexity of this disease is a barrier to developing effective
treatments, as little is known about the intricate tissue crosstalk that underlies PTOA progression. Our long-
term goal is to uncover and comprehensively characterize cellular and molecular mechanisms central to key
pathological sequalae of PTOA: synovial fibrosis, inflammation, and osteophyte formation. We will focus on
canonical Wnt/β-catenin (cWnt) signaling. cWnt overactivation has recently been implicated as a driving factor
of arthritis. Our data show that the cWnt signaling agonist R-spondin 2 (Rspo2) is strongly induced in multiple
joint tissues during PTOA, and that Rspo2 alone is sufficient to induce pathological features characteristic of
PTOA. Using single-cell RNA-seq, we profiled synovium of mice with PTOA and found that Rspo2 is produced
by synovial lining fibroblasts. We identified a novel population of pro-fibrotic cells that arise after injury and
express Lgr cell surface receptors for Rspo2. We showed that synovial fibroblasts respond to Rspo2 by
secreting cytokines that in turn activate pro-inflammatory macrophages (known to drive synovial pathology in
PTOA). Single-cell profiling also revealed a novel subset of injury-induced, Lgr-expressing osteochondral
progenitors in synovium, which we propose give rise to osteophytes. We hypothesize that Rspo2-driven cWnt
signaling mediates pathological crosstalk between joint-resident cell types to potentiate PTOA. To test this, our
aims in the K99 phase are to: 1) determine the role of Rspo2-driven cWnt signaling in the emergence and
function of pro-fibrotic synovial cells during PTOA using transgenic reporter mice, multi-omic analyses, and in
vitro differentiation assays, and 2) characterize crosstalk between cWnt-active synovial fibroblasts and pro-
inflammatory macrophages, using knockout mice and crosstalk assays. To extend upon my molecular biology
and immunology expertise, I will receive rigorous technical and conceptual training from my diverse mentorship
committee during the K99 phase, and valuable career guidance. This expert training in bioinformatics; cWnt
signaling; bone, cartilage, and synovial biology; and multi-modal imaging, will be crucial for carrying out my
K99 aims and especially critical for successfully launching my independent career. These skills will be utilized
in my R00 phase to: 3) determine how Rspo2/Lgr signaling promotes osteophyte formation in PTOA, using
tissue-specific deletion and reporter mice, and in vitro differentiation assays. This work will significantly extend
our understanding of cellular and molecular mechanisms that underpin synovial fibrosis, inflammation, and
osteophyte formation in PTOA. These insights will have meaningful, tangible outcomes for human health, by
accelerating development of effective disease-modifying treatments for PTOA sufferers.
创伤后骨关节炎(PTOA)是一种退行性关节疾病,在受伤后出现,影响数百万人
国际吧目前还没有疾病修饰治疗。PTOA是一种复杂的多组织关节疾病
以疼痛、软骨退化、滑膜炎症和纤维化以及异位骨形成为特征
称为骨赘的生长物。这种疾病固有的复杂性是开发有效治疗的障碍。
由于对PTOA进展背后的复杂组织串扰知之甚少,我们长久以来-
长期目标是揭示和全面表征细胞和分子机制的核心关键
PTOA的病理后遗症:滑膜纤维化、炎症和骨赘形成。我们将专注于
典型的Wnt/β-连环蛋白(cWnt)信号传导。cWnt过度激活最近被认为是一个驱动因素,
关节炎我们的数据表明,cWnt信号激动剂R-spondin 2(Rspo 2)在多个细胞中被强烈诱导,
在PTOA期间,Rspo 2足以诱导关节组织病理学特征,
PTOA。使用单细胞RNA-seq,我们分析了PTOA小鼠的滑膜,发现Rspo 2在PTOA小鼠的滑膜中产生。
滑膜衬里成纤维细胞。我们发现了一种新的促纤维化细胞群,它们在损伤后产生,
表达Rspo 2的Lgr细胞表面受体。我们发现滑膜成纤维细胞对Rspo 2的反应是,
分泌细胞因子,进而激活促炎性巨噬细胞(已知在炎症中驱动滑膜病理学),
PTOA)。单细胞分析也揭示了一个新的损伤诱导的,表达Lgr的骨软骨细胞亚群。
滑膜中的祖细胞,我们认为这会产生骨赘。我们假设Rspo 2驱动的cWnt
信号传导介导关节驻留细胞类型之间的病理性串扰以增强PTOA。为了验证这一点,我们
K99阶段的目标是:1)确定Rspo 2驱动的cWnt信号传导在出现中的作用,
使用转基因报告小鼠、多组学分析和免疫组化方法研究PTOA过程中促纤维化滑膜细胞的功能
体外分化测定,和2)表征cWnt活性滑膜成纤维细胞和促分化因子之间的串扰。
炎症巨噬细胞,使用敲除小鼠和串扰测定。在分子生物学上
和免疫学专业知识,我将接受严格的技术和概念培训,从我的多样化的导师
在K99阶段的委员会,和宝贵的职业指导。生物信息学专家培训; cWnt
信号;骨,软骨和滑膜生物学;和多模态成像,将是至关重要的执行我的
K99的目标,尤其是成功地启动我的独立职业生涯至关重要。这些技能将用于
在我的R 00阶段:3)确定Rspo 2/Lgr信号传导如何促进PTOA中骨赘形成,使用
组织特异性缺失和报告小鼠,以及体外分化测定。这项工作将大大扩展
我们对支撑滑膜纤维化、炎症和炎症的细胞和分子机制的理解,
PTOA骨赘形成。这些见解将对人类健康产生有意义的切实成果,
加速为PTOA患者开发有效的疾病改善治疗方法。
项目成果
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