FGFR3/fibroblast growth factor receptor 3 inhibits autophagy through decreasing the ATG12-ATG5 conjugate, leading to the delay of cartilage development in achondroplasia
FGFR3/fibroblast growth factor receptor 3 inhibits autophagy through decreasing the ATG12-ATG5 conjugate, leading to the delay of cartilage development in achondroplasia
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FGFR3/成纤维细胞生长因子受体3通过减少ATG12-ATG5缀合物抑制自噬，导致软骨发育不全的软骨发育延迟
DOI：
10.1080/15548627.2015.1091551
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发表时间：
2015-11-01
期刊：
影响因子：
13.3
通讯作者：
Chen, Lin
中科院分区：
文献类型：
--
作者：
Wang, Xiaofeng;Qi, Huabing;Chen, Lin
成纤维细胞生长因子受体3(FGFR3)是软骨内成骨的负调控因子。FGFR3的功能获得突变是导致软骨发育不全的原因，软骨发育不全是人类最常见的侏儒症遗传形式。自噬是一种进化上保守的分解代谢过程，在低氧和营养缺乏等应激条件下维持生长板中软骨细胞的活性。然而，自噬在软骨发育不全中的作用及其潜在的分子机制仍然不清楚。在这项研究中，我们发现激活的FGFR3信号抑制了体内和体外软骨细胞的自噬活性。通过胚胎骨培养系统，我们证明了自噬抑制剂3-MA或氯喹处理导致软骨生长迟缓，这与激活的FGFR3信号在软骨形成中的作用相似。此外，我们还发现FGFR3通过与ATG5结合而与ATG12-ATG5结合物相互作用。更有趣的是，FGFR3信号被发现降低ATG12-ATG5结合物的蛋白质水平。使用体外软骨分化实验系统，我们一致地证明ATG12-ATG5结合物对于软骨细胞的存活和分化是必不可少的。瞬时转染ATG5可部分逆转FGFR3对软骨细胞活性和分化的抑制作用。我们的研究结果表明，FGFR3通过降低ATG12-ATG5结合水平来抑制自噬活性，这可能在软骨发育不全的发病机制中起重要作用。
FGFR3 (fibroblast growth factor receptor 3) is a negative regulator of endochondral ossification. Gain-of-function mutations in FGFR3 are responsible for achondroplasia, the most common genetic form of dwarfism in humans. Autophagy, an evolutionarily conserved catabolic process, maintains chondrocyte viability in the growth plate under stress conditions, such as hypoxia and nutritional deficiencies. However, the role of autophagy and its underlying molecular mechanisms in achondroplasia remain elusive. In this study, we found activated FGFR3 signaling inhibited autophagic activity in chondrocytes, both in vivo and in vitro. By employing an embryonic bone culture system, we demonstrated that treatment with autophagy inhibitor 3-MA or chloroquine led to cartilage growth retardation, which mimics the effect of activated-FGFR3 signaling on chondrogenesis. Furthermore, we found that FGFR3 interacted with ATG12-ATG5 conjugate by binding to ATG5. More intriguingly, FGFR3 signaling was found to decrease the protein level of ATG12-ATG5 conjugate. Consistently, using in vitro chondrogenic differentiation assay system, we showed that the ATG12-ATG5 conjugate was essential for the viability and differentiation of chondrocytes. Transient transfection of ATG5 partially rescued FGFR3-mediated inhibition on chondrocyte viability and differentiation. Our findings reveal that FGFR3 inhibits the autophagic activity by decreasing the ATG12-ATG5 conjugate level, which may play an essential role in the pathogenesis of achondroplasia.