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: 8500208
• 负责人: Martin K Lotz
• 金额: $ 38.58万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500208
• 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/文摘

项目成果

High-mobility group box-1 protein promotes granulomatous nephritis in adenine-induced nephropathy.

• DOI: 10.1038/labinvest.2010.64
• 发表时间: 2010-06
• 期刊: Laboratory investigation; a journal of technical methods and pathology