title: Nordihydroguaiaretic acid inhibition of NFATc1 suppresses osteoclastogenesis and arthritis bone destruction in rats.
abstract: Nordihydroguaiaretic acid (NDGA) is known to have prominent anticancer activity against several cancers, and is also known to be an inhibitor of 5-lipoxygenase (5-LO). In this study, we investigated the regulatory function of NDGA on inflammatory bone destruction mediated by osteoclasts. NDGA markedly inhibited receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced formation of osteoclasts in cultures of murine osteoclast precursor cell line RAW-D cells and primary bone marrow-derived macrophages culture systems. The inhibitory effect of NDGA on osteoclastogenesis did not arise from the inhibition of 5-LO activity. NDGA did not affect MAPKs, such as p38, JNK, and NF-κB, but significantly inhibited the induction of NFATc1, a key transcription factor for osteoclastogenesis. NDGA also suppressed activation of ERK in osteoclast precursors. RANKL-induced calcium oscillation observed in osteoclast precursors was completely diminished by the addition of NDGA. In mature osteoclasts, RANKL-induced nuclear translocation of NFATc1 was clearly inhibited by NDGA treatment. Finally, in vivo studies demonstrated that administration of NDGA significantly reduced severe bone destruction and osteoclast recruitment in the ankle joint of rats with adjuvant-induced arthritis. These results indicate the potential utility of NDGA as a therapeutic agent for ameliorating inflammatory bone destruction in rheumatoid arthritis.
authors.affiliation: Division of Oral Biological Sciences, Department of Molecular Cell Biology and Oral Anatomy, Kyushu University, Fukuoka, Japan.
authors.forename: Yin-Ji
authors.initials: YJ
authors.lastname: Li
authors.forename: Akiko
authors.initials: A
authors.lastname: Kukita
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Toshio
authors.initials: T
authors.lastname: Takano
authors.forename: Pengfei
authors.initials: P
authors.lastname: Qu
authors.forename: Keisuke
authors.initials: K
authors.lastname: Sanematsu
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Ninomiya
authors.forename: Toshio
authors.initials: T
authors.lastname: Kukita
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption / Q000188:drug therapy* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D009637:Masoprocol / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010000:Osteitis / Q000188:drug therapy / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D050778:NFATC Transcription Factors; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D009637:Masoprocol