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（由申请人提供）：导致关节软骨退化的软骨细胞活化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作为修复机制的一部分高度活跃。例如，与正常人类成人关节软骨细胞 (HAC) 相比，骨关节炎 (OA) 细胞高度表达合成代谢因子，例如 TGFb 和 BMP。不幸的是，在大多数情况下，这些修复尝试都会失败，并最终发展为 OA。为什么？在当前的提案中，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 bFGF 对众所周知的单独的 IGF-1 和 BMP7 的软骨合成代谢活性以及这两种合成代谢因子在藻酸盐和软骨外植体中的组合的组合具有显着的拮抗作用。令人惊讶的是，bFGF 的这种抗组合作用不会抑制 IGF-1 和 BMP7 介导的细胞增殖。 bFGF 单独可增加增殖，与其他生长因子结合时甚至可进一步促进增殖。我们认为这是人们仍然报道 bFGF 作为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 bFGF 促进纤维软骨的形成，而纤维软骨是透明软骨的不良替代品。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代谢。 bFGF 由软骨细胞表达，储存在软骨 ECM 中，并在软骨损伤时从软骨基质中释放。最近的数据显示，与正常 HAC 相比，OA 中 bFGF 和 FGFR1 的表达高度上调。 bFGF 对 BMP/IGF-1 的显着抑制作用表明，在损伤/外伤、负荷或关节炎期间，软骨基质中 bFGF 的过度表达/释放可能会显着降低关节软骨的合成代谢活性。定义 bFGF 对 Smad 信号通路（代表细胞对 TGFb/BMP 的反应）介导的精确抑制性细胞/分子机制，将揭示在以正常合成代谢丧失为特征的情况下抑制软骨中过度 bFGF 活性的治疗益处-分解代谢平衡，例如 OA。更好地了解翻译后修饰剂 SUMO 在创伤/关节炎软骨中的调节和功能可能为骨关节炎等软骨相关关节疾病的治疗干预提供新的靶点。