FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway
FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway
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DOI：
10.1101/gad.13.11.1361
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发表时间：
1999-06-01
影响因子：
10.5
通讯作者：
Basilico, C
中科院分区：
文献类型：
--
作者：
Sahni, M;Ambrosetti, DC;Basilico, C
人类侏儒症的几种遗传形式与FGF受体3的激活突变有关，表明FGF信号传导在软骨细胞成熟和骨骼发育中起关键作用。然而，FGF影响软骨细胞增殖和分化的机制仍然知之甚少。我们发现FGF信号的激活抑制了大鼠软骨肉瘤（RCS）细胞系和原代小鼠软骨细胞的增殖。RCS细胞的FGF处理诱导STAT-1的磷酸化，其易位到细胞核，并增加细胞周期抑制剂p21 WAF 1/CIP1的表达。我们已经使用STAT-1基因敲除小鼠的原代软骨细胞来提供STAT-1功能是FGF介导的生长抑制所需的遗传证据。此外，FGF处理来自野生型和STAT（-/-）鼠胚胎的跖骨雏形在野生型中产生软骨细胞增殖和骨发育的严重损害，但在STAT-1（-/-）雏形中不产生。我们认为STAT-1介导的FGF信号转导下调软骨细胞增殖是一种稳态机制，可确保骨发育和形态发生的协调。
Several genetic forms of human dwarfism have been linked to activating mutations in FGF receptor 3, indicating that FGF signaling has a critical role in chondrocyte maturation and skeletal development. However, the mechanisms through which FGFs affect chondrocyte proliferation and differentiation remain poorly understood. We show here that activation of FGF signaling inhibits chondrocyte proliferation both in a rat chondrosarcoma (RCS) cell line and in primary murine chondrocytes. FGF treatment of RCS cells induces phosphorylation of STAT-1, its translocation to the nucleus, and an increase in the expression of the cell-cycle inhibitor p21WAF1/CIP1. We have used primary chondrocytes from STAT-1 knock-out mice to provide genetic evidence that STAT-1 function is required for the FGF mediated growth inhibition. Furthermore, FGF treatment of metatarsal rudiments from wild-type and STAT(-/-) murine embryos produces a drastic impairment of chondrocyte proliferation and bone development in wild-type, but not in STAT-1(-/-) rudiments. We propose that STAT-1 mediated down regulation of chondrocyte proliferation by FGF signaling is an homeostatic mechanism which ensures harmonious bone development and morphogenesis.