Abstract
Background & AimsAfter years of experiments and clinical studies, parathyroid hormone-related protein(PTHrP) has been shown to be a bone formation promoter that elicits rapid effects with limited adverse reaction. Recently, PTHrP was reported to promote fibrosis in rat kidney in conjunction with transforming growth factor-beta1 (TGF-β1), which is also a fibrosis promoter in liver. However, the effect of PTHrP in liver has not been determined. In this study, the promoting actions of PTHrP were first investigated in human normal hepatic stellate cells (HSC) and LX-2 cell lines.MethodsTGF-β1, alpha-smooth muscle actin (α-SMA), matrix metalloproteinase 2 (MMP-2), and collagen I mRNA were quantified by real-time polymerase chain reaction (PCR) after HSCs or LX-2 cells were treated with PTHrP(1–36) or TGF-β1. Protein levels were also assessed by western-blot analysis. Alpha-SMA were also detected by immunofluorescence, and TGF-β1 secretion was measured with enzyme-linked immunosorbent assay (ELISA) of HSC cell culture media.ResultsIn cultured human HSCs, mRNA and protein levels of α-SMA, collagen I, MMP-2, and TGF-β1 were increased by PTHrP treatment. A similar increasing pattern was also observed in LX-2 cells. Moreover, PTHrP significantly increased TGF-β1 secretion in cultured media from HSCs.ConclusionsPTHrP activated HSCs and promoted the fibrosis process in LX-2 cells. These procedures were probably mediated via TGF-β1, highlighting the potential effects of PTHrP in the liver.
Highlights
Parathyroid hormone-related protein (PTHrP) was first identified from cancers that caused hypercalcemia, but over 25 years of study, it has been demonstrated to work as a multifunctional cytokine [1]
transforming growth factor-beta1 (TGF-b1), alpha-smooth muscle actin (a-SMA), matrix metalloproteinase 2 (MMP-2), and collagen I mRNA were quantified by real-time polymerase chain reaction (PCR) after hepatic stellate cells (HSC) or LX-2 cells were treated with PTHrP(1–36) or TGF-b1
In cultured human HSCs, mRNA and protein levels of a-SMA, collagen I, MMP-2, and TGF-b1 were increased by PTHrP treatment
Summary
Parathyroid hormone-related protein (PTHrP) was first identified from cancers that caused hypercalcemia, but over 25 years of study, it has been demonstrated to work as a multifunctional cytokine [1]. Experiments have demonstrated that PTHrP promotes bone formation and is an excellent osteogenic promoter that exerts rapid effects and few adverse reactions, even after years of clinical treatments for osteoporosis (OP) [2,3,4,5]. Activation of HSCs is a key event in hepatic fibrosis, where they acquire contractility and the extracellular matrix (ECM) changes as they transform to myofibroblast-like cells [8]. These cells express the myofibroblast marker a-smooth muscle actin (a-SMA) [9,10], and synthesize fibrillar collagens. After years of experiments and clinical studies, parathyroid hormone-related protein(PTHrP) has been shown to be a bone formation promoter that elicits rapid effects with limited adverse reaction. The promoting actions of PTHrP were first investigated in human normal hepatic stellate cells (HSC) and LX-2 cell lines
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