Cbfβ mediates articular cartilage regeneration and repair in aging

这项研究的长期目标是了解骨关节炎在衰老过程中的调节机制。这个 这项研究的具体目标是表征cbfβ介导软骨的潜在机制。 骨关节炎的再生和修复。骨关节炎(OA)是最常见的关节炎形式，影响 膝盖、臀部和脊椎，给55岁之间的超过70%的美国人带来疼痛和身体限制 和70岁。目前治疗骨性关节炎的选择仍然局限于疼痛管理和手术治疗。 这是老龄化人口中的一个重大问题。最近的研究揭示了骨性关节炎的本质 并确认了一些与滑膜损伤有关的候选基因， 关节软骨和软骨下骨在骨性关节炎发病机制中的作用，包括Wnt信号。然而，根 这种疾病的原因尚不清楚。研究了骨性关节炎患者之间的基因表达模式 和正常供者，并结合已知的调控数据，庆友等人。确定了一些 转录因子和其他基因可能在骨性关节炎的发展中发挥重要作用，包括 核心结合因子β(Cbfβ)。PI的实验室已经广泛地研究了成骨细胞中CBFβ的功能和 小鼠骨骼发育过程中的软骨细胞。然而，脑血流量β在骨性关节炎发病机制中的作用 关节软骨的再生和修复仍不清楚。为了研究软骨细胞中骨性关节炎的发病机制- 针对CbFβ基因缺陷小鼠，我们建立了可诱导条件基因敲除的CbFβf/fCol2α1-creer小鼠 使用三苯氧胺注射剂。我们发现CbfβCko小鼠在3.5a龄时发生自发性骨性关节炎 几个月，在肩部、膝盖、臀部和脊椎表现出严重的OA表型。我们的数据表明 脑血流量βf/fCol2α1-creer中WnT规范信号下调，YAP表达上调 AAv-CMV-Cbfβ介导的CbFβ过表达对小鼠骨关节炎有明显的保护作用。 根据我们的初步数据，我们假设cbfβ缺陷是软骨形成的主要原因之一。 骨性关节炎退变和衰老及CBFβ过度表达促进软骨再生和修复 通过调节Wnt信号和YAP信号来调节OA。我们将通过三个具体目标来检验这一假设。在……里面 目的1、通过广泛的研究，我们将确定cbfβ在衰老关节软骨细胞动态平衡中的作用。 成年和老年、雌性和雄性CBFβf/fCol2α1-creer小鼠的生理和免疫表型分析 病理情况。在目标2中，我们将确定cbfβ在软骨再生和修复中的作用。 通过表征脑血流量β功能增益小鼠模型预防衰老中的骨性关节炎的发生。我们将剖析 CBFβ在软骨形成和关节形成过程中调节Wnt和YAP信号的机制 AIM 3中的软骨再生和修复。这项拟议的研究将为了解 骨性关节炎中CBFβ调控关节软骨WNT和YAP信号机制的研究 再生和修复。为实现研究目标，成立了一个多学科研究团队。

The long term goal of this study is to understand the mechanisms mediating osteoarthritis in aging. The specific goal of this study is to characterize the mechanism underlying how Cbfβ mediates cartilage regeneration and repair in osteoarthritis. Osteoarthritis (OA) is the most common form of arthritis affecting the knees, hips and spines, inflicting pain and physical limitation on over 70% of Americans between the age of 55 and 70. Current therapeutic options for 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 the damage of the synovium, articular cartilage, and subchondral bone in OA pathogenesis, including Wnt signaling. However, the root causes of the disease remain unclear. Having investigated the gene expression patterns between OA patients and normal donors, and in combining with the known regulation data, Qingyou et al. identified a number of transcriptional factors and other genes which may play important roles in the development of OA including Core-binding factor beta (Cbfβ). The PI’s lab has extensively study Cbfβ function in osteoblasts and chondrocytes during mouse skeletal development. Nevertheless, the function of Cbfβ in OA pathogenesis and articular cartilage regeneration and repair remains unclear. In order to study OA pathogenesis in chondrocyte- specific Cbfβ deficient mice, we generated the inducible conditional knockout (CKO) Cbfβf/fCol2α1-CreER mice using Tamoxifen injections. We discovered that Cbfβ CKO mice developed spontaneous OA at the age of 3.5 months, showing severe OA phenotype at the shoulders, knees, hips and spines. Our data demonstrated that Wnt canonical signaling was down-regulated and Yap expression was up-regulated in Cbfβf/fCol2α1-CreER mice and that Cbfβ overexpression mediated by AAV-CMV-Cbfβ has significant protection against OA. Based on our preliminary data, we hypothesize that deficiency of Cbfβ is one of the main causes of cartilage degeneration in OA and aging and that overexpression of Cbfβ enhances cartilage regeneration and repair in OA by regulating Wnt signaling and Yap signaling. We will test this hypothesis through three specific aims. In Aim 1, we will determine the roles of Cbfβ in aging articular chondrocyte homeostasis through extensive phenotypic analyses of adult and aged, female and male Cbfβf/fCol2α1-CreER mice in physiological and pathological conditions. In Aim 2, we will define the function of Cbfβ in cartilage regeneration and repair and preventing OA genesis in aging by characterizing Cbfβ gain-of-function mouse model. We will dissect the mechanism underlying how Cbfβ regulates Wnt and Yap signaling during chondrogenesis and articular cartilage regeneration and repair in Aim 3. The proposed study will provide important insights into the roles of Cbfβ in OA by elucidating the mechanism by which Cbfβ regulates Wnt and Yap signaling in articular cartilage regeneration and repair. A multidisciplinary research team been established to achieve the research goals.