Pathological Role of bFGF in Human Adult Articular Cartilage

bFGF 在人类成人关节软骨中的病理作用

• 批准号: 7847270
• 负责人: Hee-Jeong Im Sampen
• 金额: $ 4.08万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-10 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847270
• 关键词: Acute; Address; Adult; Alginates; Arthritis; BMP7 gene; Biological; Cartilage; Cartilage Matrix; Cell Proliferation; Cells; Chondrocytes; Clinical; Data; Degenerative polyarthritis; Development; Disease; Doctor of Philosophy; Employee Strikes; Enzymes; Equilibrium; Event; Exhibits; Extracellular Matrix; FGFR1 gene; Fibroblast Growth Factor 2; Fibrocartilages; Gene Targeting; Gills; Growth Factor; Health Care Costs; Homeostasis; Human; Hyaline Cartilage; Inflammation Mediators; Injury; Insulin-Like Growth Factor I; Interleukin-2; Joints; Light; MAPK14 gene; MAPK8 gene; Mechanics; Mediating; Modification; Molecular; Osteoarthrosis Deformans; Output; Pathogenesis; Pathology; Pathway interactions; Phosphorylation; Physiological; Play; Post-Translational Protein Processing; Principal Investigator; Production; Promoter Regions; Regulation; Reporting; Research Personnel; Role; Signal Pathway; Signal Transduction; Source; Stress; Subgroup; Synovial Fluid; Therapeutic; Therapeutic Intervention; Tissues; Trauma; Ubiquitin; Ubiquitination; Work; Wound Healing; Yang; arthropathies; articular cartilage; base; bone morphogenetic protein receptors; cartilage metabolism; clinically relevant; collagenase 3; combinatorial; cytokine; desensitization; disability; human disease; in vivo; joint destruction; novel; repaired; response; small molecule; transcription factor

DESCRIPTION (provided by applicant): Chondrocyte activation that results in degradation of articular cartilage is a key event in the pathogenesis of arthritis. Paradoxically, chondrocytes in damaged cartilage are highly active as part of a repair mechanism. For example, Osteoarthritic (OA) cells highly express anabolic factors, such as TGFb and BMPs compared to normal human adult articular chondrocytes (HACs). Unfortunately, in most cases, these attempts for repair fail, and eventually develop OA. Why? In the current proposal, we address this question and try to understand the potential mechanisms by which OA cells fail to repair. Recently, we reported the striking antagonistic effect of bFGF on the well-known cartilage anabolic activity of IGF-1 & BMP7 alone and in combination of these two anabolic factors in alginate and within cartilage explants. Surprisingly, this anti-combinatorial effect of bFGF does not inhibit cellular proliferation mediated by IGF-1 & BMP7. bFGF alone increases proliferation and even further promotes it when combined with other growth factors. We consider that this is the main reason why people still report bFGF as an anabolic factor for cartilage in vivo. Based on our data, we believe that bFGF promotes fibrocartilage formation which is a poor substitute of hyaline cartilage. The importance of the quality of repaired cartilage can not be overstressed. Multiple factors work in concert to control the overall metabolism of cartilage in vivo. bFGF is expressed by chondrocytes, is stored in the cartilage ECM, and is released from the cartilage matrix upon cartilage damage. More recent data revealed that the expression of bFGF and FGFR1 are highly upregulated in OA compared to normal HACs. Significant inhibitory action of bFGF on BMP/IGF-1 suggests that excessive expression/release of bFGF from the cartilage matrix during injury/trauma, with loading or in arthritis could substantially contribute to reduced anabolic activity in articular cartilage. Defining the precise inhibitory cellular/molecular mechanisms mediated by bFGF on Smad signaling pathway, which represents the cellular response to TGFb/BMP, will shed light on the therapeutic benefit by inhibition of excessive bFGF activity in cartilage in conditions characterized by loss of the normal anabolic-catabolic balance such as OA. Better understanding of the regulation and function of the posttranslational modifier SUMO in traumatic/arthritic cartilage may provide new targets for therapeutic intervention in cartilage-associated joint diseases such as OA.

描述(申请人提供)：导致关节软骨退化的软骨细胞激活是关节炎发病机制中的关键事件。矛盾的是，受损软骨中的软骨细胞高度活跃，是修复机制的一部分。例如，与正常成人关节软骨细胞(HAC)相比，骨关节炎(OA)细胞高度表达合成代谢因子，如TGFb和BMPs。不幸的是，在大多数情况下，这些修复的尝试都失败了，最终发展为骨性关节炎。为什么？在目前的提案中，我们解决了这个问题，并试图了解OA细胞无法修复的潜在机制。最近，我们报道了碱性成纤维细胞生长因子对众所周知的IGF-1和BMP7的软骨合成活性的显著拮抗作用，以及这两种合成因子在藻酸盐和软骨外植体中的联合作用。令人惊讶的是，碱性成纤维细胞生长因子的这种抗结合作用并不能抑制IGF-1和BMP7介导的细胞增殖。碱性成纤维细胞生长因子单独促进增殖，当与其他生长因子联合使用时，甚至进一步促进增殖。我们认为，这是为什么人们仍然报道bFGF是体内软骨合成代谢因子的主要原因。根据我们的数据，我们认为碱性成纤维细胞生长因子促进纤维软骨的形成，而纤维软骨是玻璃化软骨的不良替代品。修复软骨质量的重要性怎么强调都不为过。多种因素协同作用，控制体内软骨的整体新陈代谢。碱性成纤维细胞生长因子由软骨细胞表达，储存在软骨细胞外基质中，在软骨损伤时从软骨基质中释放出来。更新的数据显示，与正常的HAC相比，骨性关节炎中bFGF和FGFR1的表达高度上调。碱性成纤维细胞生长因子对BMP/IGF-1的显著抑制作用提示，在创伤/创伤、负重或关节炎过程中，软骨基质中过度表达/释放碱性成纤维细胞生长因子可能是关节软骨合成代谢活性降低的重要原因。明确bFGF对Smad信号通路(代表细胞对TGFb/BMP的反应)的确切抑制细胞/分子机制，将有助于阐明在以失去正常合成-分解代谢平衡为特征的条件下，通过抑制软骨中过量的bFGF活性而达到的治疗效果。更好地了解翻译后修饰物相扑在创伤/关节炎软骨中的调节和功能，可能为软骨相关关节疾病如骨关节炎的治疗干预提供新的靶点。