CCN proteins in cartilage formation and maintenance

CCN 蛋白在软骨形成和维护中的作用

• 批准号: 7460228
• 负责人: Karen M. Lyons
• 金额: $ 6.15万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-20 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7460228
• 关键词: Accounting; Address; Adhesives; Adult; Affect; Alleles; Arthritis; Binding Sites; Cartilage; Cells; Chondrocytes; Chondrogenesis; Condition; Defect; Development; Disease; Dysplasia; Electron Microscopy; Employee Strikes; Epiphysial cartilage; Exhibits; Extracellular Matrix; Family; Family member; Fibroblasts; Gene Expression; Gene Expression Regulation; Genes; Human; Hypertrophy; In Vitro; Integrins; Joints; Knockout Mice; Ligands; Light; Maintenance; Mediating; Mediator of activation protein; Messenger RNA; Mus; Mutation; Normal tissue morphology; Osteogenesis; Output; Phenotype; Play; Process; Production; Proliferating; Protein Family; Proteins; Regulation; Regulatory Element; Role; Signal Pathway; Signal Transduction; Skeletal system; Tamoxifen; Testing; Tissues; Transcript; Transgenic Mice; Transgenic Organisms; Ursidae Family; articular cartilage; connective tissue growth factor; in vivo; laser capture microdissection; member; mutant; novel; promoter; protein distribution; recombinase; repaired; tumor progression

Members of the CCN family are key mediators of disease processes. CCN2/CTGF (Connective Tissue Growth Factor) is the major mediator of excess ECM synthesis in all fibrotic conditions studied to date, and CCN1/Cyr61 has potent proangiogenic activities in tumor progression. These proteins are proposed to act as matricellular proteins, coordinating signals mediated by ECM-integrin interactions with otherpathways. However, which of the many in vitro activities of these proteins are physiologicallyrelevant isunknown, because their functions in normal tissue development /maintenance are undefined. Studies of targeted mice demonstrate that CCN2/CTGF is essential for chondrogenesis. Whether CCN2 mediates its effects by acting as a ligand for integrins, affecting synthesis of ECM and its modulators, and/or altering the outputs of signaling pathways in cartilage will be investigated in aim one. The consequences of loss of Ccn2 on gene expression in discrete regions of the growth plate will be investigated to test the hypotheses that Ccn2 has global effects on ECM content, and to test whether output of specific signaling pathways is impacted by loss of CCN2. Signaling pathways controlling CCN2 expression in cartilage will be identified in aim two. As Ccn2-l- mice bear a striking resemblance to Sox9+/- mice, whether CCN2 is a direct target of Sox factors will be investigated. As one of the major phenptypes of Ccn2-/- mice is psteopenia as a result of defective chondrocyte hypertrophy, these studies will also shed light on signaling pathways essential for the ability of hypertrophic cartilage to control subsequent bone formation. A key question regarding the roles of matricellular proteins is the extent to which they fulfill overlapping functions. In vitro studies suggest broadly similar activities for CCNs. However, in no case has it been shown that CCN1 and CCN2 have overlapping functions. A unique role of CCN1 in chondrogenesis and in joint formation is revealed by analysis of Ccn1 null mice. In aim three this unique joint phenotype is investigated and a Ccn1 floxed allele is used to define the role of CCN1 in cartilage. Analysis of double and compound mutants will test directly the degree to which CCN1 and 2 fulfill overlapping functions. Finally, there is compelling evidence implicating multiple CCN family members as essential for the maintenance of adult articular cartilage. Ccn2 is one of the most abundant transcripts in adult articular cartilage, and articular chondrocytes respond to CCN2, leading to repair of articular defects. In humans, loss of a related gene, CCN6, leads to a progressive pseudorheumatoid dysplasia, a severe form of arthritis, suggesting that a major shared function for CCN proteins is to maintain articular cartilage. We test the hypothesis that CCN2 is vital for the maintenance of adult cartilage using a floxed Ccn2 allele and a tamoxifen-inducible Cre recombinase.

CCN家族成员是疾病过程的关键介质。CCN2/CTGF(结缔组织