Cbf mediates articular cartilage regeneration and repair in aging

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- 相关性骨关节炎(OA)。这项研究的直接目标是描述潜在的机制 核心结合因子β在增龄相关关节软骨再生修复中的作用 骨关节炎。目前老年性骨性关节炎的治疗选择仍然局限于疼痛管理和外科手术。 干预措施代表了人口老龄化的一个重大关切。最近的研究揭示了 骨性关节炎的遗传易感性，并确认了一些参与损伤的候选基因 关节软骨，包括SOX9、YAP、WNT/β-连环蛋白信号和转化生长因子β/骨形态发生蛋白信号。然而，根 这种疾病的原因尚不清楚。在我们的初步研究中，我们发现cbfβ的表达 小鼠关节软骨中随年龄增长而减少，而出生后诱导软骨细胞特异性脑血流β缺陷 小鼠出现自发的类骨关节炎表型，其特征是关节软骨退化和 软骨下骨侵犯，随着年龄的增长而加重。值得注意的是，rna-seq数据的热图分析 显示Cbfβf/fCol2α1-Cre与衰老小鼠关节软骨有非常相似的基因变化。 与两个月龄小鼠关节软骨的表达谱进行比较。我们的qPCR数据证实 衰老相关关节软骨中骨关节炎相关基因表达的变化及脑血流量β缺陷 诱导的骨性关节炎包括Sox9、BMP7、Alk3的下调和YAP、Wnt5a/b、Wnt/β-catenin的上调 此外，腺相关病毒-巨细胞病毒-CBFβ介导的CBFβ过表达具有局部给药保护作用 小鼠的外科骨性关节炎。根据我们的初步数据，我们假设cbfβ缺陷是主要的原因之一。 增龄性骨关节炎关节软骨退变的原因及CBF-β增强关节 通过调节多个关键信号通路，包括Wnt/β-Catenin， 骨形态发生蛋白/转化生长因子β、YAP和Sox9信号通路。我们将通过三个具体目标来检验这一假设。在……里面 目的：探讨β在衰老相关关节软骨再生和修复中的作用。 成年和老年βf/faggrecan-creer小鼠和老年野生型小鼠的骨关节炎分析 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 脑血流量β在中老年关节软骨再生修复及预防骨性关节炎发生中的作用 利用AAv-CMV-Cbfβ和CbfβOEF/Faggrecan-Creer基因获得小鼠的功能 过度表达的模型。我们将剖析cbfβ增强关节软骨的机制。 WNT/β-连环蛋白、骨形态发生蛋白/转化生长因子β、YAP和Sox9信号通路的调控在再生修复中的作用 目标3.从拟议研究中获得的见解将不仅涉及基本的 关于衰老相关骨性关节炎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的治疗方法来治疗衰老相关的骨性关节炎。

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.