AB0889 Massive Elimination of Multinucleated Osteoclasts by Eupatilin is Due to Dual Inhibition of Transcription and Cytoskeletal Rearrangement. (9th June 2015)

• Record Type: Journal Article
• Authors: Baek, J.-M.; Lee, W.-S.; Yoo, W.-H.; Kim, J.-Y.; Oh, J.-M.; Lee, M.-S.; Lee, C.-H.
• Is Part Of: Annals of the rheumatic diseases. Volume 74(2015)Supplement 2
• Page Start: 1197
• Page End: 1198
• Publication Date: 2015-06-09
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2015-eular.3218
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Osteoporosis is an ageing-associated diseases requiring better therapeutic modality. Eupatilin is a major flavonoid from Artemisia. Objectives: We aimed to evaluate the effects of eupatilin on RANKL-induced osteoclast differentiation and its mechanism of action. Results: Upon stimulation prior to nuclear factor κB (RANK)-ligand (RANKL) treatment or poststimulation of bone marrow macrophages (BMCs) in the presence of RANKL with eupatilin complete blockade of RANK-dependent osteoclastogenesis was accomplished. This blockade was accompanied by inhibition of rapid phosphorylation of Akt, GSK3b, ERK and IkB as well as downregulation of c-Fos and NFATc1 at protein levels, suggesting that transcriptional suppression is a key acting mechanism on the anti-osteoclastogenesis. Transient reporter assays or gain of function assays confirmed that eupatilin was, indeed, a potent transcriptional inhibitor in osteoclasts (OC). Surprisingly, when multinucleated osteoclasts (MNCs) were cultured on bone scaffolds in the presence of eupatilin bone resorption activity was also completely blocked by dismantling actin ring, suggesting that another major acting site of eupatilin is cytoskeletal rearrangement. The eupatilin-treated MNCs revealed a shrunk cytoplasm and accumulation of multi-nuclei, eventually becoming fibroblast-like cells. No apoptosis occurred. Inhibition of phosphorylation of cofilin by eupatilin suggests that actin may play an important role in the catastrophic morphological change of MNCs. Human OC were similarly responded to eupatilin. When eupatilin was administered to LPS-induced osteoporotic mice after manifestation of osteoporosis, it was capable of preventing bone loss. The ovariectomized (OVX) mice remarkably exhibited bone protection effects. Conclusions: Taken together, eupatilin is an effective versatile therapeutic intervention for osteoporosis as dual blockaders; 1) transcriptional suppression of c-Fos and NFATc1 of differentiating OC and 2) inhibition of actin rearrangement of pathogenic MNCs. Disclosure of Interest: None declared