Negative feedback loop in the Bim-caspase-3 axis regulating apoptosis and activity of osteoclasts

Hidetoshi Wakeyama, Toru Akiyama, Katsuhiko Takahashi, Hitoshi Amano, Yuho Kadono, Masaki Nakamura, Yasushi Oshima, Hiroyuki Itabe, Keiichi I. Nakayama, Keiko Nakayama, Kozo Nakamura, Sakae Tanaka

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Proapoptotic Bcl-2 family member Bim plays an essential role in the osteoclast apoptosis and is degraded through ubiquitin/proteasome pathways in a caspase-3-dependent manner. This negative feedback loop in the Bim-caspase-3 axis is important for regulating the survival and activity of osteoclasts. Introduction: Bim is a member of the proapoptotic Bcl-2 family and regulates the mitochondrial apoptosis pathway. Bim expression is post-translationally regulated in osteoclasts (OCs) through ubiquitin/proteasome pathways, and Bim is critical for their survival and activity. Materials and Methods: Time-course of change in the expression of Bim in the course of OC apoptosis was examined, and the effect of various proteinase inhibitors on the degradation of Bim was analyzed. The role of caspase-3 and caspase-7 on Bim degradation was studied using RNA interference technique and caspase-3-/- mice. Results: Bim was degraded after caspase-3 activation, which was suppressed by a caspase inhibitor and a proteasome inhibitor. Bim degradation was suppressed by gene knockdown of caspase-3 or in caspase-3-/- OCs but not by caspase-7 knockdown. OCs generated from caspase-3-/- bone marrow cells exhibited a shorter life span and higher bone-resorbing activity than normal OCs. Association of Bim with E3 ubiquitin ligase c-Cbl was suppressed by gene knockdown of caspase-3 or in caspase-3-/- OCs. Actin ring formation and cathepsin K expression were promoted in caspase-3-/- OCs. Conclusions: Caspase-3 negatively regulates Bim expression by stimulating its degradation through ubiquitin/ proteasome pathways, thus creating a negative feedback loop in the Bim-caspase axis.

Original languageEnglish
Pages (from-to)1631-1639
Number of pages9
JournalJournal of Bone and Mineral Research
Volume22
Issue number10
DOIs
Publication statusPublished - Oct 1 2007

Fingerprint

Osteoclasts
Caspase 3
Apoptosis
Proteasome Endopeptidase Complex
Ubiquitin
Gene Knockdown Techniques
Caspase 7
Cathepsin K
Proteasome Inhibitors
Caspase Inhibitors
Ubiquitin-Protein Ligases
Caspases
RNA Interference
Bone Marrow Cells
Actins
Peptide Hydrolases

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Wakeyama, H., Akiyama, T., Takahashi, K., Amano, H., Kadono, Y., Nakamura, M., ... Tanaka, S. (2007). Negative feedback loop in the Bim-caspase-3 axis regulating apoptosis and activity of osteoclasts. Journal of Bone and Mineral Research, 22(10), 1631-1639. https://doi.org/10.1359/jbmr.070619

Negative feedback loop in the Bim-caspase-3 axis regulating apoptosis and activity of osteoclasts. / Wakeyama, Hidetoshi; Akiyama, Toru; Takahashi, Katsuhiko; Amano, Hitoshi; Kadono, Yuho; Nakamura, Masaki; Oshima, Yasushi; Itabe, Hiroyuki; Nakayama, Keiichi I.; Nakayama, Keiko; Nakamura, Kozo; Tanaka, Sakae.

In: Journal of Bone and Mineral Research, Vol. 22, No. 10, 01.10.2007, p. 1631-1639.

Research output: Contribution to journalArticle

Wakeyama, H, Akiyama, T, Takahashi, K, Amano, H, Kadono, Y, Nakamura, M, Oshima, Y, Itabe, H, Nakayama, KI, Nakayama, K, Nakamura, K & Tanaka, S 2007, 'Negative feedback loop in the Bim-caspase-3 axis regulating apoptosis and activity of osteoclasts', Journal of Bone and Mineral Research, vol. 22, no. 10, pp. 1631-1639. https://doi.org/10.1359/jbmr.070619
Wakeyama, Hidetoshi ; Akiyama, Toru ; Takahashi, Katsuhiko ; Amano, Hitoshi ; Kadono, Yuho ; Nakamura, Masaki ; Oshima, Yasushi ; Itabe, Hiroyuki ; Nakayama, Keiichi I. ; Nakayama, Keiko ; Nakamura, Kozo ; Tanaka, Sakae. / Negative feedback loop in the Bim-caspase-3 axis regulating apoptosis and activity of osteoclasts. In: Journal of Bone and Mineral Research. 2007 ; Vol. 22, No. 10. pp. 1631-1639.
@article{d8b5691e25094131a9384f7382b00cf6,
title = "Negative feedback loop in the Bim-caspase-3 axis regulating apoptosis and activity of osteoclasts",
abstract = "Proapoptotic Bcl-2 family member Bim plays an essential role in the osteoclast apoptosis and is degraded through ubiquitin/proteasome pathways in a caspase-3-dependent manner. This negative feedback loop in the Bim-caspase-3 axis is important for regulating the survival and activity of osteoclasts. Introduction: Bim is a member of the proapoptotic Bcl-2 family and regulates the mitochondrial apoptosis pathway. Bim expression is post-translationally regulated in osteoclasts (OCs) through ubiquitin/proteasome pathways, and Bim is critical for their survival and activity. Materials and Methods: Time-course of change in the expression of Bim in the course of OC apoptosis was examined, and the effect of various proteinase inhibitors on the degradation of Bim was analyzed. The role of caspase-3 and caspase-7 on Bim degradation was studied using RNA interference technique and caspase-3-/- mice. Results: Bim was degraded after caspase-3 activation, which was suppressed by a caspase inhibitor and a proteasome inhibitor. Bim degradation was suppressed by gene knockdown of caspase-3 or in caspase-3-/- OCs but not by caspase-7 knockdown. OCs generated from caspase-3-/- bone marrow cells exhibited a shorter life span and higher bone-resorbing activity than normal OCs. Association of Bim with E3 ubiquitin ligase c-Cbl was suppressed by gene knockdown of caspase-3 or in caspase-3-/- OCs. Actin ring formation and cathepsin K expression were promoted in caspase-3-/- OCs. Conclusions: Caspase-3 negatively regulates Bim expression by stimulating its degradation through ubiquitin/ proteasome pathways, thus creating a negative feedback loop in the Bim-caspase axis.",
author = "Hidetoshi Wakeyama and Toru Akiyama and Katsuhiko Takahashi and Hitoshi Amano and Yuho Kadono and Masaki Nakamura and Yasushi Oshima and Hiroyuki Itabe and Nakayama, {Keiichi I.} and Keiko Nakayama and Kozo Nakamura and Sakae Tanaka",
year = "2007",
month = "10",
day = "1",
doi = "10.1359/jbmr.070619",
language = "English",
volume = "22",
pages = "1631--1639",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",
number = "10",

}

TY - JOUR

T1 - Negative feedback loop in the Bim-caspase-3 axis regulating apoptosis and activity of osteoclasts

AU - Wakeyama, Hidetoshi

AU - Akiyama, Toru

AU - Takahashi, Katsuhiko

AU - Amano, Hitoshi

AU - Kadono, Yuho

AU - Nakamura, Masaki

AU - Oshima, Yasushi

AU - Itabe, Hiroyuki

AU - Nakayama, Keiichi I.

AU - Nakayama, Keiko

AU - Nakamura, Kozo

AU - Tanaka, Sakae

PY - 2007/10/1

Y1 - 2007/10/1

N2 - Proapoptotic Bcl-2 family member Bim plays an essential role in the osteoclast apoptosis and is degraded through ubiquitin/proteasome pathways in a caspase-3-dependent manner. This negative feedback loop in the Bim-caspase-3 axis is important for regulating the survival and activity of osteoclasts. Introduction: Bim is a member of the proapoptotic Bcl-2 family and regulates the mitochondrial apoptosis pathway. Bim expression is post-translationally regulated in osteoclasts (OCs) through ubiquitin/proteasome pathways, and Bim is critical for their survival and activity. Materials and Methods: Time-course of change in the expression of Bim in the course of OC apoptosis was examined, and the effect of various proteinase inhibitors on the degradation of Bim was analyzed. The role of caspase-3 and caspase-7 on Bim degradation was studied using RNA interference technique and caspase-3-/- mice. Results: Bim was degraded after caspase-3 activation, which was suppressed by a caspase inhibitor and a proteasome inhibitor. Bim degradation was suppressed by gene knockdown of caspase-3 or in caspase-3-/- OCs but not by caspase-7 knockdown. OCs generated from caspase-3-/- bone marrow cells exhibited a shorter life span and higher bone-resorbing activity than normal OCs. Association of Bim with E3 ubiquitin ligase c-Cbl was suppressed by gene knockdown of caspase-3 or in caspase-3-/- OCs. Actin ring formation and cathepsin K expression were promoted in caspase-3-/- OCs. Conclusions: Caspase-3 negatively regulates Bim expression by stimulating its degradation through ubiquitin/ proteasome pathways, thus creating a negative feedback loop in the Bim-caspase axis.

AB - Proapoptotic Bcl-2 family member Bim plays an essential role in the osteoclast apoptosis and is degraded through ubiquitin/proteasome pathways in a caspase-3-dependent manner. This negative feedback loop in the Bim-caspase-3 axis is important for regulating the survival and activity of osteoclasts. Introduction: Bim is a member of the proapoptotic Bcl-2 family and regulates the mitochondrial apoptosis pathway. Bim expression is post-translationally regulated in osteoclasts (OCs) through ubiquitin/proteasome pathways, and Bim is critical for their survival and activity. Materials and Methods: Time-course of change in the expression of Bim in the course of OC apoptosis was examined, and the effect of various proteinase inhibitors on the degradation of Bim was analyzed. The role of caspase-3 and caspase-7 on Bim degradation was studied using RNA interference technique and caspase-3-/- mice. Results: Bim was degraded after caspase-3 activation, which was suppressed by a caspase inhibitor and a proteasome inhibitor. Bim degradation was suppressed by gene knockdown of caspase-3 or in caspase-3-/- OCs but not by caspase-7 knockdown. OCs generated from caspase-3-/- bone marrow cells exhibited a shorter life span and higher bone-resorbing activity than normal OCs. Association of Bim with E3 ubiquitin ligase c-Cbl was suppressed by gene knockdown of caspase-3 or in caspase-3-/- OCs. Actin ring formation and cathepsin K expression were promoted in caspase-3-/- OCs. Conclusions: Caspase-3 negatively regulates Bim expression by stimulating its degradation through ubiquitin/ proteasome pathways, thus creating a negative feedback loop in the Bim-caspase axis.

UR - http://www.scopus.com/inward/record.url?scp=38449119999&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=38449119999&partnerID=8YFLogxK

U2 - 10.1359/jbmr.070619

DO - 10.1359/jbmr.070619

M3 - Article

C2 - 17592965

AN - SCOPUS:38449119999

VL - 22

SP - 1631

EP - 1639

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 10

ER -