HMGB2 in cartilage homeostasis, aging and osteoarthritis

HMGB2 在软骨稳态、衰老和骨关节炎中的作用

• 批准号: 8277985
• 负责人: Martin K Lotz
• 金额: $ 40.61万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277985
• 关键词: Address; Adenoviruses; Affect; Aging; Arthritis; Binding Sites; Biological Assay; Biomechanics; Bone remodeling; Cartilage; Cell Differentiation process; Cell Survival; Cell physiology; Cells; Cellularity; Chondrocytes; Collagen; Complex; Cyclin D1; Data; Defect; Degenerative polyarthritis; Development; Disease; Elderly; Enhancers; Etiology; Evolution; Excision; FOS gene; Gene Deletion; Gene Expression; Genes; Genetic; Goals; HMGB2 gene; Homeostasis; Human; In Vitro; Intra-Articular Injections; Joints; Knee; Knee joint; Knock-out; Lead; Lesion; Lubrication; Maps; Matrix Metalloproteinases; Medial meniscus structure; Mesenchymal Stem Cells; Molecular; Monitor; Mus; Osteoarthrosis Deformans; Pathogenesis; Pathway interactions; Pattern; Phase; Phenotype; Population; Prevention; Preventive; Process; Proteins; Regulation; Relative (related person); Research; Risk Factors; Role; Site; Structure; Surface; Therapeutic; Time; Tissue Engineering; Wild Type Mouse; age related; aggrecanase; arthropathies; articular cartilage; bcl-1 Genes; cartilage cell; chromatin immunoprecipitation; chromatin protein; congenic; disability; early onset; in vivo; insight; joint function; knock-down; notch protein; overexpression; recombinase; response

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.

6.项目总结/摘要 骨关节炎（OA）是最常见的关节疾病和残疾的主要原因。衰老是主要风险 骨关节炎的一个重要因素是软骨表面区（SZ）的破坏。分子机制 确定SZ中细胞的独特表型是未知的，并提供有关初始 软骨表面缺陷是有限的。我们的初步研究表明，染色质蛋白HMGB 2是 仅在关节软骨的SZ中表达。我们检查了Hmgb 2-/-小鼠，发现更严重的OA 与野生型（WT）小鼠相比。在人类和WT小鼠关节中，存在老化相关的减少， HMGB 2表达丧失，随后软骨表面发生退行性变化。这些发现支持 我们假设HMGB 2参与软骨内稳态和与衰老相关的HMGB 2表达丧失， 是参与SZ和早期OA破坏的机制。 这项研究的目的是研究与衰老相关的HMGB 2减少如何影响软骨 完整性和解决HMGB 2的分子和细胞机制。 目标1.小鼠和人关节中的HMGB 2缺乏。我们将分析发病，演变和模式， Hmgb 2-/-小鼠软骨退变和检测Hmgb 2-/-小鼠OA发病机制 参与自发性和手术诱导的OA。这些发现将得到证实，与人类关节 软骨 目标2.关节软骨细胞中的HMGB 2。我们将描述表型和分化状态， HMGB 2表达细胞。将在培养的细胞中进行HMGB 2表达调控的研究。 我们将确定HMGB 2在调节SZ中的存活和生物合成反应中的作用， 软骨细胞 目标3。HMGB 2调节细胞功能的机制：与Lef-1和β-连环蛋白的相互作用。我们将 绘制HMGB 2和Lef-1的物理相互作用中所涉及的基本基序。我们将讨论SS的功能- 连环蛋白与HMGB 2的相互作用以及Lef-1依赖基因、SZP和存活基因的表达。 通过条件性敲除ss-连环蛋白，获得ss-连环蛋白的表面区域特异性缺失， 关节内注射表达Cre重组酶的腺病毒。 拟议的研究有可能产生新的见解的分子机制，控制 SZ软骨细胞独特的分化状态。这些信息不仅与OA有关， 软骨组织工程拟议的研究将为早期退行性变的机制提供见解。 关节软骨的变化，并可能允许开发的预防和治疗策略的OA。