Identification of Fibroblast Growth Factor-18 as a Molecule to Protect Adult Articular Cartilage by Gene Expression Profiling*
Identification of Fibroblast Growth Factor-18 as a Molecule to Protect Adult Articular Cartilage by Gene Expression Profiling*
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DOI：
10.1074/jbc.m113.524090
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发表时间：
2014-04-04
影响因子：
4.8
通讯作者：
Kawaguchi, Hiroshi
中科院分区：
文献类型：
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作者：
Mori, Yoshifumi;Saito, Taku;Kawaguchi, Hiroshi
背景：成人关节软骨损伤的预防和治疗至关重要。结果：微阵列分析鉴定了Fgf 18，其抑制软骨中聚集蛋白聚糖的释放并促进软骨细胞的增殖。关节内注射rhFGF 18预防大鼠骨关节炎模型中的软骨退变。结论：Fgf 18通过表达TIMP 1对成人关节软骨具有保护作用。重要性：Fgf 18可能代表一种治疗剂，为确定基因，维持成人关节软骨的稳态和再生其病变，我们最初比较了四种类型的软骨细胞：关节（AA）与生长板（AG）的软骨细胞在成年大鼠，和浅层（IS）与深层（ID）的骨骺软骨在幼年大鼠的软骨细胞。微阵列分析显示，40个和186个基因的AA/AG和IS/ID的表达比分别高10倍，16个基因的AA/AG和IS/ID的比例均为10倍。通过实时荧光定量RT-PCR分析验证了结果。其中Hoxd 1、Fgf 18和Esm 1在AA中的表达强于IS。fgf 18是一种细胞外分泌因子，可减少软骨中糖胺聚糖的释放和消耗，并促进关节软骨细胞的增殖。fgf 18在成年大鼠关节软骨细胞中呈强表达。在手术大鼠骨关节炎模型中，在手术后3周给予重组人FGF 18（rhFGF 18）每周一次注射，在手术后6周和9周以剂量依赖性方式防止软骨变性，在10 g/周的rhFGF 18下具有显著效果。作为潜在的机制，rhFGF 18强烈上调Timp 1在细胞和器官培养物中的表达，并且通过添加Timp 1的抗体恢复rhFGF 18对聚集蛋白聚糖释放的抑制。总之，我们已经确定FGF 18作为一种分子，保护关节软骨的基因表达谱，和抗代谢作用可能至少部分介导的Timp 1的表达。
Background: Prevention of adult articular cartilage and treatment of its lesions are essential. Results: Microarray analyses identified Fgf18, which inhibits aggrecan release from cartilage and enhances proliferation of chondrocytes. The intra-articular injection of rhFGF18 prevented cartilage degeneration in a rat osteoarthritis model. Conclusion: Fgf18 protects adult articular cartilage through Timp1 expression. Significance: Fgf18 may represent a therapeutic agent for osteoarthritis.To identify genes that maintain the homeostasis of adult articular cartilage and regenerate its lesions, we initially compared four types of chondrocytes: articular (AA) versus growth plate (AG) cartilage chondrocytes in adult rats, and superficial layer (IS) versus deep layer (ID) chondrocytes of epiphyseal cartilage in infant rats. Microarray analyses revealed that 40 and 186 genes had 10-fold higher expression ratios of AA/AG and IS/ID, respectively, and 16 genes showed 10-fold of both AA/AG and IS/ID ratios. The results were validated by real-time RT-PCR analysis. Among them, Hoxd1, Fgf18, and Esm1 were expressed more strongly in AA than in IS. Fgf18 was the extracellular and secreted factor that decreased glycosaminoglycan release and depletion from the cartilage, and enhanced proliferation of articular chondrocytes. Fgf18 was strongly expressed in the articular cartilage chondrocytes of adult rats. In a surgical rat osteoarthritis model, a once-weekly injection of recombinant human FGF18 (rhFGF18) given 3 weeks after surgery prevented cartilage degeneration in a dose-dependent manner at 6 and 9 weeks after surgery, with significant effect at 10 g/week of rhFGF18. As the underlying mechanism, rhFGF18 strongly up-regulated Timp1 expression in the cell and organ cultures, and inhibition of aggrecan release by rhFGF18 was restored by addition of an antibody to Timp1. In conclusion, we have identified Fgf18 as a molecule that protects articular cartilage by gene expression profiling, and the anticatabolic effects may at least partially be mediated by the Timp1 expression.