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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Heme oxygenase-1 (HO-1)/carbon monoxide (CO) axis suppresses RANKL-induced osteoclastic differentiation by inhibiting redox-sensitive NF-κB activation

  • Bak, Sun-Uk (Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University) ;
  • Kim, Suji (Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University) ;
  • Hwang, Hae-Jun (Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University) ;
  • Yun, Jung-A (Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University) ;
  • Kim, Wan-Sung (Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University) ;
  • Won, Moo-Ho (Department of Neurobiology, School of Medicine, Kangwon National University) ;
  • Kim, Ji-Yoon (Department of Anesthesiology and Pain Medicine, Hanyang University Hospital) ;
  • Ha, Kwon-Soo (Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University) ;
  • Kwon, Young-Guen (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University) ;
  • Kim, Young-Myeong (Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University)
  • Received : 2016.12.19
  • Accepted : 2017.01.13
  • Published : 2017.02.28
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Abstract

Heme oxygenase (HO-1) catalyzes heme to carbon monoxide (CO), biliverdin/bilirubin, and iron and is known to prevent the pathogenesis of several human diseases. We assessed the beneficial effect of heme degradation products on osteoclastogenesis induced by receptor activator of NF-${\kappa}B$ ligand (RANKL). Treatment of RAW264.7 cells with CORM-2 (a CO donor) and bilirubin, but not with iron, decreased RANKL-induced osteoclastogenesis, with CORM-2 having a more potent anti-osteogenic effect. CORM-2 also inhibited RANKL-induced osteoclastogenesis and osteoclastic resorption activity in marrow-derived macrophages. Treatment with hemin, a HO-1 inducer, strongly inhibited RANKL-induced osteoclastogenesis in wild-type macrophages, but was ineffective in $HO-1^{+/-}$ cells. CORM-2 reduced RANKL-induced NFATc1 expression by inhibiting IKK-dependent NF-${\kappa}B$ activation and reactive oxygen species production. These results suggest that CO potently inhibits RANKL-induced osteoclastogenesis by inhibiting redox-sensitive NF-${\kappa}B$-mediated NFATc1 expression. Our findings indicate that HO-1/CO can act as an anti-resorption agent and reduce bone loss by blocking osteoclast differentiation.

Keywords

References

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