Deletion of the PH-domain and Leucine-rich Repeat Protein Phosphatase 1 (Phlpp1) Increases Fibroblast Growth Factor (Fgf) 18 Expression and Promotes Chondrocyte Proliferation
Deletion of the PH-domain and Leucine-rich Repeat Protein Phosphatase 1 (Phlpp1) Increases Fibroblast Growth Factor (Fgf) 18 Expression and Promotes Chondrocyte Proliferation
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DOI：
10.1074/jbc.m114.612937
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发表时间：
2015-06-26
影响因子：
4.8
通讯作者：
Westendorf, Jennifer J.
中科院分区：
文献类型：
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作者：
Bradley, Elizabeth W.;Carpio, Lomeli R.;Westendorf, Jennifer J.
背景：Phlpp 1是一种抑制Akt 2和其他信号通路的肿瘤抑制因子。结果如下：在Phlpp 1（-/-）小鼠中，软骨细胞增殖、基质产生、Akt 2磷酸化和Fgf 18/Erk 1/2信号传导增加，但转录因子FoxO 1的水平降低。结论：Phlpp 1缺陷增加Akt 2活性，从而降低FoxO 1水平并诱导Fgf 18表达以刺激Erk 1/2活性和软骨细胞增殖。重要性：Phlpp 1抑制可促进软骨再生。软骨内骨化协调脊椎动物骨骼的形成，通常在肌肉骨骼系统的疾病和修复过程中被诱导。在这里，我们表明，蛋白磷酸酶Phlpp 1调节软骨内骨化。Phlpp 1基因敲除小鼠表现出骨量减少和生长板的显著变化，包括BrdU掺入和基质产生增加。在离体培养的Phlpp 1（-/-）软骨细胞中，已知的Phlpp 1底物Akt 2、PKC和p70 S6激酶的磷酸化增强。此外，Phlpp 1缺陷减少FoxO 1水平，导致Fgf 18的表达增加，Mek/Erk活性和软骨细胞代谢活性。Phlpp抑制剂还增加基质含量、Fgf 18产生和Erk 1/2磷酸化。Fgfr信号的化学抑制废除升高Erk 1/2磷酸化和代谢活性在Phlpp 1-null文化。这些结果表明，Phlpp 1通过多种机制控制软骨形成，Phlpp 1抑制可能是促进软骨再生和修复的策略。
Background: Phlpp1 is a tumor suppressor that represses Akt2 and other signaling pathways. Results: Chondrocyte proliferation, matrix production, Akt2 phosphorylation, and Fgf18/Erk1/2 signaling were increased in Phlpp1(-/-) mice, but levels of the transcription factor FoxO1 were reduced. Conclusion: Phlpp1 deficiency increases Akt2 activity, which diminishes FoxO1 levels and induces Fgf18 expression to stimulate Erk1/2 activity and chondrocyte proliferation. Significance: Phlpp1 inhibition may promote cartilage regeneration.Endochondral ossification orchestrates formation of the vertebrate skeleton and is often induced during disease and repair processes of the musculoskeletal system. Here we show that the protein phosphatase Phlpp1 regulates endochondral ossification. Phlpp1 null mice exhibit decreased bone mass and notable changes in the growth plate, including increased BrdU incorporation and matrix production. Phosphorylation of known Phlpp1 substrates, Akt2, PKC, and p70 S6 kinase, were enhanced in ex vivo cultured Phlpp1(-/-) chondrocytes. Furthermore, Phlpp1 deficiency diminished FoxO1 levels leading to increased expression of Fgf18, Mek/Erk activity, and chondrocyte metabolic activity. Phlpp inhibitors also increased matrix content, Fgf18 production and Erk1/2 phosphorylation. Chemical inhibition of Fgfr-signaling abrogated elevated Erk1/2 phosphorylation and metabolic activity in Phlpp1-null cultures. These results demonstrate that Phlpp1 controls chondrogenesis via multiple mechanisms and that Phlpp1 inhibition could be a strategy to promote cartilage regeneration and repair.