Nordihydroguaiaretic acid inhibition of NFATc1 suppresses osteoclastogenesis and arthritis bone destruction in rats

• Published in: Laboratory investigation 2012-12, Vol.92 (12), p.1777-1787
• Main Authors: Li, Yin-Ji, Kukita, Akiko, Watanabe, Toshiyuki, Takano, Toshio, Qu, Pengfei, Sanematsu, Keisuke, Ninomiya, Yuzo, Kukita, Toshio
• Format: Article
• Language: English
• Subjects: 631/136/818; 692/699/249/1313/498; 692/700/565/1436; adjuvant arthritis; Animals; Arthritis, Experimental - drug therapy; Arthritis, Experimental - metabolism; Arthritis, Experimental - pathology; Biological and medical sciences; Biotechnology; bone destruction; Bone Resorption - drug therapy; Bone Resorption - metabolism; calcium oscillation; Calcium Signaling - drug effects; Calcium Signaling - genetics; Cell Differentiation - drug effects; Cell Line; Diseases of the osteoarticular system; Dose-Response Relationship, Drug; Female; Fundamental and applied biological sciences. Psychology; Investigative techniques, diagnostic techniques (general aspects); Laboratory Medicine; Male; Masoprocol - pharmacology; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Miscellaneous. Osteoarticular involvement in other diseases; NDGA; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; NFATc1; Osteitis - drug therapy; Osteitis - metabolism; Osteoclasts - metabolism; Pathology; RANK Ligand - metabolism; RANKL; Rats; Rats, Sprague-Dawley; research-article
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2012.134

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.