FGFR3 down-regulates PTH/PTHrP receptor gene expression by mediating JAK/STAT signaling in chondrocytic cell line.
FGFR3 down-regulates PTH/PTHrP receptor gene expression by mediating JAK/STAT signaling in chondrocytic cell line.
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DOI：
10.1093/jmicro/dfq002
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发表时间：
2010-06
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影响因子：
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通讯作者：
Minqi Li;Yukie Seki;Paulo H L Freitas;M. Nagata;T. Kojima;S. Sultana;Sobhan Ubaidus;T. Maeda
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文献类型：
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作者：
Minqi Li;Yukie Seki;Paulo H L Freitas;M. Nagata;T. Kojima;S. Sultana;Sobhan Ubaidus;T. Maeda
由甲状旁腺激素（PTH）相关肽（PTHrP）、PTH/PTHrP受体和成纤维细胞生长因子受体3 （FGFR3）组成的信号轴在软骨细胞增殖中起核心作用。印度刺猬（IHH）基因在早期肥大软骨细胞中正常表达，其负反馈回路被证明可调节PTH/PTHrP受体信号传导。在这项研究中，我们检测了fgfr3转染的软骨细胞系CFK2中PTH/PTHrP受体基因表达的调控。在这些细胞上无法证实IHH的表达，因此没有肥厚分化。此外，在转染FGFR3 cDNA的CFK2细胞中，PTH/PTHrP受体（总mRNA减少75%）和PTHrP基因（减少50%）的表达减少。有趣的是，我们证实了转染细胞的细胞生长显著减少，凋亡增加。转染FGFR3 cDNA的CFK2细胞细胞核中检测到STAT1，表明JAK/STAT信号通路占主导地位。在过表达FGFR3的CFK2细胞中，PTH/PTHrP受体基因的减少可以通过JAK3抑制剂（WHI-P131）部分阻断，但不能通过MAPK抑制剂（SB203580）或JAK2抑制剂（AG490）阻断。总之，这些发现表明FGFR3通过JAK/STAT信号在软骨细胞中下调PTH/PTHrP受体基因表达。
The signaling axis comprising the parathyroid hormone (PTH)-related peptide (PTHrP), the PTH/PTHrP receptor and the fibroblast growth factor receptor 3 (FGFR3) plays a central role in chondrocyte proliferation. The Indian hedgehog (IHH) gene is normally expressed in early hypertrophic chondrocytes, and its negative feedback loop was shown to regulate PTH/PTHrP receptor signaling. In this study, we examined the regulation of PTH/PTHrP receptor gene expression in a FGFR3-transfected chondrocytic cell line, CFK2. Expression of IHH could not be verified on these cells, with consequent absence of hypertrophic differentiation. Also, expression of the PTH/PTHrP receptor (75% reduction of total mRNA) and the PTHrP (50% reduction) genes was reduced in CFK2 cells transfected with FGFR3 cDNA. Interestingly, we verified significant reduction in cell growth and increased apoptosis in the transfected cells. STAT1 was detected in the nuclei of the CFK2 cells transfected with FGFR3 cDNA, indicating predominance of the JAK/STAT signaling pathway. The reduction in PTH/PTHrP receptor gene in CFK2 cells overexpressing FGFR3 was partially blocked by treatment with an inhibitor of JAK3 (WHI-P131), but not with an inhibitor of MAPK (SB203580) or JAK2 (AG490). Altogether, these findings suggest that FGFR3 down-regulates PTH/PTHrP receptor gene expression via the JAK/STAT signaling in chondrocytic cells.