Activated hepatic stellate cells are dependent on self-collagen, cleaved by membrane type 1 matrix metalloproteinase for their growth

Naoko Kubo Birukawa, Kazuyuki Murase, Yasushi Sato, Akemi Kosaka, Akihiro Yoneda, Hiroki Nishita, Ryosuke Fujita, Miyuki Nishimura, Takafumi Ninomiya, Keiko Kajiwara, Miyono Miyazaki, Yusuke Nakashima, Sigenori Ota, Yuya Murakami, Yasunobu Tanaka, Kenjiro Minomi, Yasuaki Tamura, Yoshiro Niitsu

Research output: Contribution to journalArticle

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Abstract

Stellate cells are distributed throughout organs, where, upon chronic damage, they become activated and proliferate to secrete collagen, which results in organ fibrosis. An intriguing property of hepatic stellate cells (HSCs) is that they undergo apoptosis when collagen is resolved by stopping tissue damage or by treatment, even though the mechanisms are unknown. Here we disclose the fact that HSCs, normal diploid cells, acquired dependence on collagen for their growth during the transition from quiescent to active states. The intramolecular RGD motifs of collagen were exposed by cleavage with their own membrane type 1 matrix metalloproteinase (MT1-MMP). The following evidence supports this conclusion. When rat activated HSCs (aHSCs) were transduced with siRNA against the collagen-specific chaperone gp46 to inhibit collagen secretion, the cells underwent autophagy followed by apoptosis. Concomitantly, the growth of aHSCs was suppressed, whereas that of quiescent HSCs was not. These in vitro results are compatible with the in vivo observation that apoptosis of aHSCs was induced in cirrhotic livers of rats treated with siRNAgp46. siRNA against MT1-MMP and addition of tissue inhibitor of metalloproteinase 2 (TIMP-2), which mainly inhibits MT1-MMP, also significantly suppressed the growth of aHSCs in vitro . The RGD inhibitors echistatin and GRGDS peptide and siRNA against the RGD receptor αVβ1 resulted in the inhibition of aHSCs growth. Transduction of siRNAs against gp46, αVβ1, and MT1-MMP to aHSCs inhibited the survival signal of PI3K/AKT/IκB. These results could provide novel antifibrosis strategies.

Original languageEnglish
Pages (from-to)20209-20221
Number of pages13
JournalJournal of Biological Chemistry
Volume289
Issue number29
DOIs
Publication statusPublished - Jan 1 2014

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Matrix Metalloproteinase 14
Hepatic Stellate Cells
Collagen
Growth
Small Interfering RNA
Apoptosis
glycyl-arginyl-glycyl-aspartyl-serine
Rats
Tissue Inhibitor of Metalloproteinase-2
Autophagy
Diploidy
Phosphatidylinositol 3-Kinases
Liver
Fibrosis
Observation
Tissue
Peptides

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Activated hepatic stellate cells are dependent on self-collagen, cleaved by membrane type 1 matrix metalloproteinase for their growth. / Birukawa, Naoko Kubo; Murase, Kazuyuki; Sato, Yasushi; Kosaka, Akemi; Yoneda, Akihiro; Nishita, Hiroki; Fujita, Ryosuke; Nishimura, Miyuki; Ninomiya, Takafumi; Kajiwara, Keiko; Miyazaki, Miyono; Nakashima, Yusuke; Ota, Sigenori; Murakami, Yuya; Tanaka, Yasunobu; Minomi, Kenjiro; Tamura, Yasuaki; Niitsu, Yoshiro.

In: Journal of Biological Chemistry, Vol. 289, No. 29, 01.01.2014, p. 20209-20221.

Research output: Contribution to journalArticle

Birukawa, NK, Murase, K, Sato, Y, Kosaka, A, Yoneda, A, Nishita, H, Fujita, R, Nishimura, M, Ninomiya, T, Kajiwara, K, Miyazaki, M, Nakashima, Y, Ota, S, Murakami, Y, Tanaka, Y, Minomi, K, Tamura, Y & Niitsu, Y 2014, 'Activated hepatic stellate cells are dependent on self-collagen, cleaved by membrane type 1 matrix metalloproteinase for their growth', Journal of Biological Chemistry, vol. 289, no. 29, pp. 20209-20221. https://doi.org/10.1074/jbc.M113.544494
Birukawa, Naoko Kubo ; Murase, Kazuyuki ; Sato, Yasushi ; Kosaka, Akemi ; Yoneda, Akihiro ; Nishita, Hiroki ; Fujita, Ryosuke ; Nishimura, Miyuki ; Ninomiya, Takafumi ; Kajiwara, Keiko ; Miyazaki, Miyono ; Nakashima, Yusuke ; Ota, Sigenori ; Murakami, Yuya ; Tanaka, Yasunobu ; Minomi, Kenjiro ; Tamura, Yasuaki ; Niitsu, Yoshiro. / Activated hepatic stellate cells are dependent on self-collagen, cleaved by membrane type 1 matrix metalloproteinase for their growth. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 29. pp. 20209-20221.
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AU - Birukawa, Naoko Kubo

AU - Murase, Kazuyuki

AU - Sato, Yasushi

AU - Kosaka, Akemi

AU - Yoneda, Akihiro

AU - Nishita, Hiroki

AU - Fujita, Ryosuke

AU - Nishimura, Miyuki

AU - Ninomiya, Takafumi

AU - Kajiwara, Keiko

AU - Miyazaki, Miyono

AU - Nakashima, Yusuke

AU - Ota, Sigenori

AU - Murakami, Yuya

AU - Tanaka, Yasunobu

AU - Minomi, Kenjiro

AU - Tamura, Yasuaki

AU - Niitsu, Yoshiro

PY - 2014/1/1

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