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This galley proof is being listed electronically before publishing the final manuscript (It's not final version).

Heme oxygenase-1 (HO-1)/carbon monoxide (CO) axis suppresses RANKL-induced osteoclastic differentiation by inhibiting redox-sensitive NF-リB activation
Sun-Uk Bak1, Suji Kim1, Hae-Jun Hwang1, Jung-A Yun1, Wan-Sung Kim1, Moo-Ho Won2, Ji-Yoon Kim3, Kwon-Soo Ha1, Young-Guen Kwon4, Young-Myeong Kim1,*
1Molecular and Cellular Biochemistry and 2Neurobiology, School of Medicine, Kangwon National University,
3Anesthesiology and Pain Medicine, Hanyang University Hospital,
4Biochemistry, College of Life Science and Biotechnology, Yonsei University
Heme oxygenase (HO-1) catalyzes heme to carbon monoxide (CO), biliverdin/bilirubin, and iron. It prevents the pathogenesis of several human diseases. Here we assessed the beneficial effect of heme degradation products on osteoclastogenesis induced by receptor activator of NF-リ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 not effectively in HO-1+/- cells. CORM-2 reduced RANKL-induced NFATc1 expression by inhibiting IKK-dependent NF-リB activation and reactive oxygen species production. These results suggest that CO has a potent inhibitory effect on RANKL-induced osteoclastogenesis by inhibiting redox-sensitive NF-リB-mediated NFATc1 expression. Our findings indicate that HO-1/CO can act as an anti-resorption agent to reduce bone loss by blocking osteoclast differentiation.
Abstract, Accepted Manuscript(in press) [Submitted on December 19, 2016, Accepted on January 13, 2017]
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