Suppression of RANKL-dependent heme oxygenase-1 is required for high mobility group box 1 release and osteoclastogenesis

Eiko Sakai, Megumi Shimada-Sugawara, Kazuhisa Nishishita, Yutaka Fukuma, Mariko Naito, Kuniaki Okamoto, Koji Nakayama, Takayuki Tsukuba

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)


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 languageEnglish
Pages (from-to)486-498
Number of pages13
JournalJournal of Cellular Biochemistry
Issue number2
Publication statusPublished - Feb 2012
Externally publishedYes


  • Caspase-3
  • Heme oxygenase
  • High mobility group box 1
  • Osteoclastogenesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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