HMGB2 in cartilage homeostasis, aging and osteoarthritis

6.项目摘要/摘要 骨性关节炎是最常见的关节疾病，也是致残的主要原因。老龄化是主要风险 骨性关节炎的因素，始于软骨表面区(SZ)的破坏。分子机制 确定SZ细胞的独特表型是未知的，并说明了最初的原因 软骨表面的缺陷是有限的。我们的初步研究表明，染色质蛋白HMGB2 仅在关节软骨的SZ区表达。我们检查了Hmgb2-/-小鼠，发现更严重的骨性关节炎 与野生型(WT)小鼠相比。在人类和WT小鼠的关节中，与衰老相关的减少和 HMGB2表达缺失后软骨表面出现退行性改变。这些发现支持 HMGB2参与软骨内稳态和增龄性HMGB2表达缺失的假说 是破坏深圳特区和早期骨性关节炎的一种机制。 这项拟议的研究的目标是调查与衰老相关的HMGB2的减少如何影响软骨 整合并阐述HMGB2的分子和细胞机制。 目的1.小鼠和人关节中HMGB2缺乏症。我们将分析疾病的发生、演变和模式 Hmgb2-/-小鼠软骨退变及Hmgb2-/-小鼠骨关节炎发病机制探讨 参与自发性和外科手术诱发的骨性关节炎。这些发现将得到人类关节的证实 软骨。 目的2.HMGB2在关节软骨细胞中的表达。我们将对其表型和分化状态进行鉴定 HMGB2表达细胞。HMGB2在培养细胞中的表达调控研究 我们将确定HMGB2在调节SZ细胞存活和生物合成反应中的作用 软骨细胞。 目的3.HMGB2调节细胞功能的机制：与Lef-1和ss-catenin的相互作用。我们会 绘制参与HMGB2和Lef-1物理相互作用的基本基序。我们将讨论ss-的功能- 连环蛋白与HMGB2的相互作用及Lef-1依赖基因、SZP和生存基因的表达。 通过有条件地敲除ss-catenin，将获得ss-catenin的表层区带特异性缺失 关节腔内注射表达Cre重组酶的腺病毒。 拟议中的研究有可能对控制 SZ软骨细胞独特的分化状态。这一信息不仅与办公自动化有关，而且还与 软骨组织工程。拟议的研究将为早期退变的机制提供见解。 在关节软骨的变化，并可能使预防和治疗策略的发展为骨关节炎。

6. PROJECT SUMMARY/ABSTRACT Osteoarthritis (OA) is the most prevalent joint disease and a major cause of disability. Aging is the major risk factor for OA which begins with disruption of the cartilage superficial zone (SZ). Molecular mechanisms that determine the unique phenotype of cells in the SZ are unknown and information on causes of the initial cartilage surface defects is limited. Our preliminary studies show that the chromatin protein HMGB2 is exclusively expressed in the SZ of articular cartilage. We examined Hmgb2-/- mice and found more severe OA as compared to wild-type (WT) mice. In human and WT mouse joints there is an aging-related reduction and loss of HMGB2 expression followed by degenerative changes in the cartilage surface. These findings support our hypothesis that HMGB2 is involved in cartilage homeostasis and aging-related loss of HMGB2 expression is a mechanism involved in disruption of the SZ and early OA. The goals of the proposed study are to investigate how aging-related reduction of HMGB2 affects cartilage integrity and address molecular and cellular mechanisms of HMGB2. Aim 1. HMGB2 deficiency in murine and human joints. We will analyze onset, evolution and patterns of cartilage degeneration in Hmgb2-/- mice and examine mechanisms of OA pathogenesis in Hmgb2-/- mice involved in spontaneous and surgically induced OA. These findings will be confirmed with human articular cartilage. Aim 2. HMGB2 in articular chondrocytes. We will characterize phenotype and differentiation status of HMGB2-expressing cells. Studies will be performed on regulation of HMGB2 expression in cultured chondrocytes and we will determine the role of HMGB2 in regulating survival and biosynthetic responses in SZ chondrocytes. Aim 3. Mechanisms of HMGB2 regulation of cell function: interactions with Lef-1 and ss-catenin. We will map essential motifs involved in the physical interaction of HMGB2 and Lef-1. We will address function of ss- catenin interaction with HMGB2 and in expression of Lef-1 dependent genes, SZP and survival genes. Superficial zone-specific deletion of ss-catenin will be obtained by conditional knock out of ss-catenin by intraarticular injection of adenovirus expressing Cre recombinase. The proposed studies have the potential to generate new insight into molecular mechanisms that control the unique differentiation status of SZ chondrocytes. This information will not only be relevant to OA but also to cartilage tissue engineering. The proposed studies will provide insights into mechanisms of early degenerative changes in the articular cartilage and may permit development of preventive and therapeutic strategies for OA.