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Metalloproteinase inhibitor TIMP‐1 affects hepatocyte cell cycle via HGF activation in murine liver regeneration
Author(s) -
Mohammed Fazilat F.,
Pennington Caroline J.,
Kassiri Zamaneh,
Rubin Jeffrey S.,
Soloway Paul D.,
Ruther Ulrich,
Edwards Dylan R.,
Khokha Rama
Publication year - 2005
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20618
Subject(s) - hepatocyte growth factor , hepatocyte , matrix metalloproteinase , liver regeneration , microbiology and biotechnology , biology , cell growth , hepatocyte growth factor receptor , growth factor , cell cycle , tissue inhibitor of metalloproteinase , extracellular matrix , regeneration (biology) , chemistry , c met , endocrinology , cell , receptor , biochemistry , in vitro
Liver regeneration depends on timely restoration of cellular mass while orchestrating structural matrix remodeling. Matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) are known to regulate the extracellular matrix (ECM) turnover and, more recently, the processing of growth factors and cytokines. We have previously demonstrated that TIMP‐1 inhibits preneoplastic hepatocyte proliferation by attenuating growth factor bioavailability. In the present study, we examined the role of TIMP‐1 in de novo hepatocyte cell division during liver regeneration. Comprehensive real‐time reverse‐transcriptase polymerase chain reaction analyses of regenerating livers revealed significant inductions in the messenger RNA of TIMP‐1, TIMP‐3, TIMP‐4, MMP‐2, MMP‐9, MMP‐13, MMP‐14, and MMP‐24, while MMP‐15 expression was significantly reduced. Induction of TIMP‐1 occurred during the peak of hepatocyte DNA synthesis. Studies using genetically altered mice revealed that TIMP‐1 loss of function accelerated hepatocyte cell cycle progression. This finding was demonstrated by earlier expression of cyclin D1, proliferating cell nuclear antigen, and phosphorylated histone H3, which mark the G 1 ‐S, S, and M phase, respectively. Conversely, TIMP‐1 gain of function delayed cell cycle progression. MMP activity was increased in the absence of Timp‐1 . Examination of hepatocyte growth factor (HGF), and its receptor Met, both of which provide a mitogenic signal for hepatocyte division, showed increased HGF activity in Timp‐1 −/− –regenerating livers. HGF is released from the ECM and is proteolytically processed to its active form. Active HGF was elevated in Timp‐1 −/− mice, leading to increased immunostaining of phosphorylated Met as well as activation of a downstream effector, p38. In conclusion , TIMP‐1 is a novel negative regulator of HGF activity during liver regeneration. (H EPATOLOGY 2005.)