Abstract
The differentiation of osteoclasts is regulated by several essential cytokines, such as receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony-stimulating factor. Recently, high mobility group box 1 (HMGB1), a chromatin protein, also has been identified as one of these osteoclast differentiation cytokines. However, the molecular mechanisms that control HMGB1 release from osteoclast precursor cells are not known. Here, we report that RANKL-induced suppression of heme oxygenase-1 (HO-1), a heme-degrading enzyme, promotes HMGB1 release during osteoclastogenesis. In contrast, induction of HO-1 with hemin or curcumin in bone marrow-derived macrophages or RAW-D murine osteoclast precursor cells inhibited osteoclastogenesis and suppressed HMGB1 release. Since an inhibitor for p38 mitogen-activated protein kinase (MAPK) prevented the RANKL-mediated HO-1 suppression and extracellular release of HMGB1, these effects were p38 MAPK-dependent. Moreover, suppression of HO-1 in RAW-D cells by RNA interference promoted the activation of caspase-3 and HMGB1 release, whereas overexpression of HO-1 inhibited caspase-3 activation as well as HMGB1 release. Furthermore, these effects were regulated by redox conditions since antioxidant N-acetylcysteine abolished the HO-1/HMGB1/caspase-3 axis. These results suggest that RANKLdependent HO-1 suppression leads to caspase-3 activation and HMGB1 release during osteoclastogenesis.
| Original language | English |
|---|---|
| Pages (from-to) | 486-498 |
| Number of pages | 13 |
| Journal | Journal of Cellular Biochemistry |
| Volume | 113 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Feb 2012 |
| Externally published | Yes |
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Keywords
- Caspase-3
- Heme oxygenase
- High mobility group box 1
- Osteoclastogenesis
- RANKL
ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
Cite this
Suppression of RANKL-dependent heme oxygenase-1 is required for high mobility group box 1 release and osteoclastogenesis. / Sakai, Eiko; Shimada-Sugawara, Megumi; Nishishita, Kazuhisa; Fukuma, Yutaka; Naito, Mariko; Okamoto, Kuniaki; Nakayama, Koji; Tsukuba, Takayuki.
In: Journal of Cellular Biochemistry, Vol. 113, No. 2, 02.2012, p. 486-498.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Suppression of RANKL-dependent heme oxygenase-1 is required for high mobility group box 1 release and osteoclastogenesis
AU - Sakai, Eiko
AU - Shimada-Sugawara, Megumi
AU - Nishishita, Kazuhisa
AU - Fukuma, Yutaka
AU - Naito, Mariko
AU - Okamoto, Kuniaki
AU - Nakayama, Koji
AU - Tsukuba, Takayuki
PY - 2012/2
Y1 - 2012/2
N2 - The differentiation of osteoclasts is regulated by several essential cytokines, such as receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony-stimulating factor. Recently, high mobility group box 1 (HMGB1), a chromatin protein, also has been identified as one of these osteoclast differentiation cytokines. However, the molecular mechanisms that control HMGB1 release from osteoclast precursor cells are not known. Here, we report that RANKL-induced suppression of heme oxygenase-1 (HO-1), a heme-degrading enzyme, promotes HMGB1 release during osteoclastogenesis. In contrast, induction of HO-1 with hemin or curcumin in bone marrow-derived macrophages or RAW-D murine osteoclast precursor cells inhibited osteoclastogenesis and suppressed HMGB1 release. Since an inhibitor for p38 mitogen-activated protein kinase (MAPK) prevented the RANKL-mediated HO-1 suppression and extracellular release of HMGB1, these effects were p38 MAPK-dependent. Moreover, suppression of HO-1 in RAW-D cells by RNA interference promoted the activation of caspase-3 and HMGB1 release, whereas overexpression of HO-1 inhibited caspase-3 activation as well as HMGB1 release. Furthermore, these effects were regulated by redox conditions since antioxidant N-acetylcysteine abolished the HO-1/HMGB1/caspase-3 axis. These results suggest that RANKLdependent HO-1 suppression leads to caspase-3 activation and HMGB1 release during osteoclastogenesis.
AB - The differentiation of osteoclasts is regulated by several essential cytokines, such as receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony-stimulating factor. Recently, high mobility group box 1 (HMGB1), a chromatin protein, also has been identified as one of these osteoclast differentiation cytokines. However, the molecular mechanisms that control HMGB1 release from osteoclast precursor cells are not known. Here, we report that RANKL-induced suppression of heme oxygenase-1 (HO-1), a heme-degrading enzyme, promotes HMGB1 release during osteoclastogenesis. In contrast, induction of HO-1 with hemin or curcumin in bone marrow-derived macrophages or RAW-D murine osteoclast precursor cells inhibited osteoclastogenesis and suppressed HMGB1 release. Since an inhibitor for p38 mitogen-activated protein kinase (MAPK) prevented the RANKL-mediated HO-1 suppression and extracellular release of HMGB1, these effects were p38 MAPK-dependent. Moreover, suppression of HO-1 in RAW-D cells by RNA interference promoted the activation of caspase-3 and HMGB1 release, whereas overexpression of HO-1 inhibited caspase-3 activation as well as HMGB1 release. Furthermore, these effects were regulated by redox conditions since antioxidant N-acetylcysteine abolished the HO-1/HMGB1/caspase-3 axis. These results suggest that RANKLdependent HO-1 suppression leads to caspase-3 activation and HMGB1 release during osteoclastogenesis.
KW - Caspase-3
KW - Heme oxygenase
KW - High mobility group box 1
KW - Osteoclastogenesis
KW - RANKL
UR - http://www.scopus.com/inward/record.url?scp=84855554307&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84855554307&partnerID=8YFLogxK
U2 - 10.1002/jcb.23372
DO - 10.1002/jcb.23372
M3 - Article
VL - 113
SP - 486
EP - 498
JO - Journal of Cellular Biochemistry
JF - Journal of Cellular Biochemistry
SN - 0730-2312
IS - 2
ER -