Elsevier

Laboratory Investigation

Volume 97, Issue 9, September 2017, Pages 1020-1032
Laboratory Investigation

Article
Paired related homeobox protein 1 regulates PDGF-induced chemotaxis of hepatic stellate cells in liver fibrosis

https://doi.org/10.1038/labinvest.2017.65Get rights and content
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Abstract

Activation of the platelet-derived growth factor (PDGF)/PDGF beta receptor (PDGFβR) axis has a critical role in liver fibrosis. However, the mechanisms that regulate the PDGF signaling are yet to be elucidated. The present study demonstrates that paired related homeobox protein 1 (Prrx1) is involved in PDGF-dependent hepatic stellate cell (HSCs) migration via modulation of the expression of metalloproteinases MMP2 and MMP9. PDGF elevated the level of Prrx1 through the activation of ERK/Sp1 and PI3K/Akt/Ets1 pathways. In vivo, an adenoviral-mediated Prrx1 shRNA administration attenuated liver fibrosis in thioacetamide-induced fibrotic models. These studies reveal a role of Prrx1 as a modulator of PDGF-dependent signaling in HSCs, and inhibiting its expression may offer a therapeutic approach for hepatic fibrosis.

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Supplementary Information accompanies the paper on the Laboratory Investigation website

Supplementary information The online version of this article (doi:10.1038/labinvest.2017.65) contains supplementary material, which is available to authorized users.

Jiazhi Liao and Dean Tian: These authors contributed equally to this work.

This study demonstrates that paired related homeobox protein 1 (Prrx1) acts as a critical downstream molecule in PDGF signaling pathway and plays a major role in the recruitment of PDGF-dependent hepatic stellate cells via modulation of matrix metalloproteinases 2 and 9. Additionally, knockdown of Prrx1 attenuates liver fibrosis in animal models.