PTHrP/PTHR1 and TGF-β Levels Are Inversely Associated in Liver Regeneration

Yanna Cao, Hongting Zhang, Guohua Zhang, Xianghua Liu, Nicholas Ferraro, Lindsey Jackson, B Mark Evers, Miriam Falzon, Tien Ko

Abstract


Background. Transforming growth factor (TGF)-β provides growth control in liver regeneration. We have recently demonstrated that TGF-β induced parathyroid hormone-related protein (PTHrP) expression and secretion, and PTHrP mediated TGF-β-induced apoptosis in liver cells. However, whether PTHrP signaling pathway is altered during liver regeneration is unknown. Therefore we used a murine hepatectomy model in this study and tested the hypothesis that both PTHrP and TGF-β signaling pathways are upregulated during liver regeneration.

    Methods. Swiss Webster mice received 70% hepatectomy or sham operation and euthanized at different time points post-surgery for analyses. Liver regeneration was determined by liver/body weight and proliferating cell nuclear antigen (PCNA) staining. mRNA levels of TGF-β1, TGF-β receptors, PTHrP, and PTHrP receptor 1 (PTHR1) were measured by real-time quantitative PCR. Protein levels of TGF-β1 were measured by ELISA and PTHrP and PTHR1 were measured by Western blotting.

      Results. After 70% hepatectomy, the liver regeneration began at 24 hours and was restored to 82% of original liver mass at day 7. TGF-β1 and its receptor levels increased at 24 and 48 hours after hepatectomy, while PTHrP levels decreased at 12 hours and PTHR1 levels decreased at 12, 24 and 48 hours after hepatectomy. The levels of these molecules returned to similar levels as that in sham animals thereafter.

    Conclusion. We demonstrated that an upregulation of the TGF-β and its receptors were associated with a down-regulation of PTHrP/PTHR1 expression during liver regeneration, which may contribute to hepatocyte proliferation and regeneration after hepatectomy.


Keywords


TGF-β; Parathyroid hormone-related protein; Liver regeneration

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References


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DOI: http://dx.doi.org/10.3968/gh.v2i1.6175

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