Abstract
Osteopontin (OPN) is an important component of the extracellular matrix (ECM), which promotes liver fibrosis and has been described as a biomarker for its severity. Previously, we have demonstrated that Sex-determining region Y-box 9 (SOX9) is ectopically expressed during activation of hepatic stellate cells (HSC) when it is responsible for the production of type 1 collagen, which causes scar formation in liver fibrosis. Here, we demonstrate that SOX9 regulates OPN. During normal development and in the mature liver, SOX9 and OPN are coexpressed in the biliary duct. In rodent and human models of fibrosis, both proteins were increased and colocalized to fibrotic regions in vivo and in culture-activated HSCs. SOX9 bound a conserved upstream region of the OPN gene, and abrogation of Sox9 in HSCs significantly decreased OPN production. Hedgehog (Hh) signaling has previously been shown to regulate OPN expression directly by glioblastoma (GLI) 1. Our data indicate that in models of liver fibrosis, Hh signaling more likely acts through SOX9 to modulate OPN. In contrast to Gli2 and Gli3, Gli1 is sparse in HSCs and is not increased upon activation. Furthermore, reduction of GLI2, but not GLI3, decreased the expression of both SOX9 and OPN, whereas overexpressing SOX9 or constitutively active GLI2 could rescue the antagonistic effects of cyclopamine on OPN expression. Conclusion: These data reinforce SOX9, downstream of Hh signaling, as a core factor mediating the expression of ECM components involved in liver fibrosis. Understanding the role and regulation of SOX9 during liver fibrosis will provide insight into its potential modulation as an antifibrotic therapy or as a means of identifying potential ECM targets, similar to OPN, as biomarkers of fibrosis. (Hepatology 2012;56:1108–1116)
Highlights
Fibrosis of the liver is characterized by excessive extracellular matrix (ECM) deposition
We have shown that the transcription factor, sex-determining region Y-box 9 (SOX9), becomes ectopically expressed in activated hepatic stellate cells (HSC), where it is responsible for COL1 production.[17]
As reported by others,[10,14] Opn expression was induced $60-fold and its protein increased as rat hepatic stellate cells (rHSCs) became activated on tissue culture plastic over 2 weeks, paralleling the induction of Sox[9] and the sequential increase in Col[1] (Fig. 3A,B)
Summary
Fibrosis of the liver is characterized by excessive extracellular matrix (ECM) deposition. One of the major cell types responsible for this is the hepatic stellate cell (HSC).[1,2] In response to injury, HSCs become activated into proliferative myofibroblasts, migrate into the surrounding parenchymal cells, and secrete tissue-damaging ECM, the major component of which is type 1 collagen (COL1). We have shown that the transcription factor, sex-determining region Y-box 9 (SOX9), becomes ectopically expressed in activated HSCs, where it is responsible for COL1 production.[17] During development, SOX9 has diverse roles regulating the expression of a number of genes encoding ECM proteins.[18]
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