Cbf mediates articular cartilage regeneration and repair in aging
Cbf mediates articular cartilage regeneration and repair in aging
批准号:
10405827
负责人:
Wei Chen
金额:
$41.69万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-08-01 至 2024-04-30
关键词:
AddressAdultAffectAgeAgingAmericanArthritisBMP2 geneBMP7 geneBindingBinding SitesCandidate Disease GeneCell Culture SystemCellsChIP-seqChondrocytesCore-Binding FactorCytomegalovirusDataDegenerative polyarthritisDiseaseFoundationsGene ExpressionGene Expression ProfileGenesGenetic Predisposition to DiseaseGoalsHip region structureInflammationJointsKneeLightMedial meniscus structureMediatingModelingMusNatural regenerationNatureOperative Surgical ProceduresPainPain managementPathogenesisPathologicPhenotypePhysiologicalPlant RootsPlayRNA analysisRoleShoulderSignal PathwaySignal TransductionSystemTestingTherapeuticTranscriptional RegulationTransforming Growth Factor betaTransgenic OrganismsVertebral columnWild Type Mouseagedaging populationarticular cartilagebasebeta catenincartilage degradationcartilage regenerationcartilage repairdesignearly onsetgain of functiongenome-wideinsightloss of functionmouse genomemouse modelnovel therapeutic interventionoverexpressionpostnatalpreventpromoterregenerativesubchondral bonetherapeutically effectivetranscriptome sequencing
中文摘要
这项研究的长期目标是开发一种更安全,更有效的治疗方法来治愈衰老-
骨关节炎(OA)。本研究的直接目标是描述
核心结合因子β(Cbfβ)如何介导衰老相关关节软骨再生和修复
OA。目前,年龄相关性OA的治疗选择仍限于疼痛管理和手术治疗。
干预是人口老龄化的一个重要问题。最近的研究揭示了
OA遗传易感性的性质,并证实了一些候选基因参与的损害,
关节软骨中Sox 9、雅普、Wnt/β-catenin信号通路和TGFβ/BMP信号通路。然而,根
这种疾病的病因尚不清楚。在我们的初步研究中,我们发现Cbfβ的表达,
随着年龄的增长,小鼠关节软骨中的Cbf β表达降低,而出生后诱导的软骨细胞特异性Cbfβ缺乏
小鼠出现了以关节软骨降解为特征的自发性OA样表型,
软骨下骨侵入,随年龄增长而加重。值得注意的是,RNA测序数据的热图分析
结果表明,Cbfβf/fCol 2 α1-Cre基因与衰老小鼠关节软骨基因的变化非常相似,
与两个月大的小鼠关节软骨的表达谱进行比较。我们的qPCR数据证实
OA相关基因在衰老相关和Cbfβ缺乏的关节软骨中的表达变化
OA诱导后Sox 9、BMP 7、ALK 3表达下调,雅普、Wnt 5a/B、Wnt/β-catenin表达上调
BMP 2/4。此外,AAV-CMV-Cbfβ介导的Cbfβ过表达与局部给药保护了Cbfβ的表达。
小鼠手术OA。根据我们的初步数据,我们假设Cbfβ的缺乏是主要的原因之一,
Cbfβ是老年性骨关节炎(OA)关节软骨退变的主要原因,
软骨再生和修复通过调节多种关键信号通路,包括Wnt/β-连环蛋白,
BMP/TGFβ、雅普和Sox 9信号通路。我们将通过三个具体目标来检验这一假设。在
目的1,我们确定Cbfβ在关节软骨再生和修复中的作用,
通过分析成年和老年Cbfβf/fAggrecan-CreER小鼠以及老年野生型小鼠,
生理和病理条件通过功能丧失的方法。在目标2中,我们描述了
Cbfβ在成人和老年人关节软骨再生修复及预防OA发生中的作用
通过使用AAV-CMV-Cbfβ和CbfβOEf/fAggrecan-CreER基因的功能获得方法在小鼠中的表达
过表达模型。我们将剖析Cbfβ如何增强关节软骨的机制,
通过调节Wnt/β-catenin、BMP/TGFβ、雅普和Sox 9信号通路,
Aim 3中的老化相关OA。从拟议的研究中获得的见解不仅将解决基本问题,
关于衰老相关OA发病机制的科学问题,也将为
最终目标是促进设计更安全和新颖的治疗方法,用于治疗衰老相关的OA。
英文摘要
The long term goal of this study is to develop a safer and more effective therapeutic approach to cure aging-
associated osteoarthritis (OA). The immediate goal of this study is to characterize the mechanism underlying
how core-binding factor beta (Cbfβ) mediates articular cartilage regeneration and repair in aging-associated
OA. Current therapeutic options for aging-associated OA are still limited to pain management and surgical
intervention representing a significant concern in the aging population. Recent studies have shed light on the
nature of OA genetic susceptibility and confirmed a number of candidate genes involved in damage of the
articular cartilage, including Sox9, YAP, Wnt/β-catenin signaling and TGFβ/BMP signaling. However, the root
causes of the disease remain unclear. In our preliminary studies, we found that the expression of Cbfβ
decreases with age in mouse articular cartilage, while postnatal induced chondrocyte-specific Cbfβ-deficient
mice developed spontaneous OA-like phenotype characterized by articular cartilage degradation and
subchondral bone intrusion, which was exacerbated with age. Notably, heatmap analysis of RNA-seq data
showed that Cbfβf/fCol2α1-Cre and aging mice articular cartilage share very similar changes in the gene
expression profiles compared with that of two-month-old mouse articular cartilage. Our qPCR data confirmed
that the OA related gene expression changes in articular cartilage of aging-associated and Cbfβ deficiency
induced OA included downregulated Sox9, BMP7, ALK3 and upregulated Yap, Wnt5a/b, Wnt/β-catenin
BMP2/4. In addition, AAV-CMV-Cbfβ mediated Cbfβ overexpression with local administration protected against
surgical OA in mice. Based on our preliminary data, we hypothesize that deficiency of Cbfβ is one of the main
causes of articular cartilage degeneration in aging-associated osteoarthritis (OA), and Cbfβ enhances articular
cartilage regeneration and repair by modulating multiple key signaling pathways, including Wnt/β-catenin,
BMP/TGFβ, YAP and Sox9 signaling pathways. We will test this hypothesis through three specific aims. In
Aim1, We determine the roles of Cbfβ in articular cartilage regeneration and repair in aging-associated
osteoarthritis through analyses of adult and aged Cbfβf/fAggrecan-CreER mice, and aged wild type mice in
physiological and pathological conditions via a loss-of-function approach. In Aim 2, we characterize the
function of Cbfβ in articular cartilage regeneration and repair and preventing OA genesis in adult and aged
mice via a gain-of-function approach using AAV-CMV-Cbfβ and CbfβOEf/fAggrecan-CreER gene
overexpression models. We will dissect the mechanism underlying how Cbfβ enhances articular cartilage
regeneration and repair by regulating the Wnt/β-catenin, BMP/TGFβ, YAP, and Sox9 signaling pathways in
aging-associated OA in Aim 3. Insights gained from the proposed study will not only address the basic
scientific question about the pathogenesis of aging-associated OA, but also will provide the foundation for the
ultimate goal of facilitating the design of safer and novel therapeutic approach for aging-associated OA.
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