Fibroblast growth factors 2, 4, and 8 exert both negative and positive effects on limb, frontonasal, and mandibular chondrogenesis via MEK-ERK activation
Fibroblast growth factors 2, 4, and 8 exert both negative and positive effects on limb, frontonasal, and mandibular chondrogenesis via MEK-ERK activation
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DOI：
10.1002/jcp.20923
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发表时间：
2007-04-01
影响因子：
5.6
通讯作者：
Kulyk, William M.
中科院分区：
文献类型：
--
作者：
Bobick, Brent E.;Thornhill, Tasha M.;Kulyk, William M.
成纤维细胞生长因子（FGF）及其受体在胚胎肢体和面部原基的生长、形态发生和软骨形成中起着重要的调节作用。然而，在多能间充质细胞分化为软骨细胞的过程中，bFGF信号的细胞内途径目前尚不清楚。我们目前的研究表明，FGF 8，4，和2-治疗发挥抑制和刺激作用的软骨分化的微团培养制备的鸡胚翅芽，额鼻质量，和下颌弓间充质细胞通过激活的MEK-ERK丝裂原活化蛋白激酶（MAPK）级联反应。在培养阶段23/24和阶段28/29翅芽间充质，以及阶段24/25和阶段28/29额鼻细胞，FGF治疗抑郁症软骨基质的生产和三个软骨特异性基因的转录水平降低：col 2a 1，聚集蛋白聚糖，和sox 9。相反，FGF处理增加了24/25期和28/29期下颌间充质培养物中的软骨分化。在所有类型的细胞中，FGF处理提高内源性ERK磷酸化。此外，当用MEK抑制剂UO 126处理培养物或用显性阴性ERK 2转染培养物时，FGF对下颌骨软骨形成的刺激作用以及FGF对翼间充质和24/25期额鼻细胞的抑制作用都被完全阻断。因此，MEK-ERK活化是信号转导途径的重要组成部分，其介导FGF 8、4和2对胚胎肢体、下颌骨和早期额鼻间充质细胞中的软骨形成的正面和负面影响。有趣的是，FGF对晚期额鼻细胞的作用似乎是通过ERK非依赖性系统传递的。
Fibroblast growth factors (FGFs) and their receptors play fundamental roles regulating growth, morphogenesis, and cartilage formation in embryonic limbs and facial primordia. However, the intracellular pathways that transduce FGF signals during the differentiation of pluripotentmesenchymal cells into chondrocytes are currently unknown. Our present study demonstrates that FGF8,4, and 2-treatments exert both inhibitory and stimulatory effects on cartilage differentiation in micromass cultures prepared from mesenchymal cells of the chick embryo wing bud, frontonasal mass, and mandibular arch through activation of the MEK-ERK mitogen-activated protein kinase (MAPK) cascade. In cultures of stage 23/24 and stage 28/29 wing bud mesenchyme, as well as stage 24/25 and stage 28/29 frontonasal cells, FGF treatments depressed cartilage matrix production and decreased transcript levels for three cartilage-specific genes: col2a1, aggrecan, and sox9. Conversely, FGF treatment increased cartilage differentiation in cultures of stage 24/25 and stage 28/29 mandibular mesenchyme. In all cell types, FGF treatment elevated endogenous ERK phosphorylation. Moreover, both the stimulatory effects of FGFs on mandibular chondrogenesis, as well as the inhibitory effects of FGFs on wing mesenchyme and stage 24/25 frontonasal cells, were completely blocked when cultures were treated with MEK inhibitor UO 126 or transfected with dominant negative ERK2. Thus, MEK-ERK activation is an essential component of the signal transduction pathway that mediates both positive and negative effects of FGFs 8, 4, and 2 on chondrogenesis in embryonic limb, mandibular, and early-stage frontonasal mesenchyme cells. Interestingly, the effects of FGF on late-stage frontonasal cells appear to be relayed by an ERK-independent system.