PMID- 27288918 OWN - NLM STAT- MEDLINE DCOM- 20170424 LR - 20181202 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 23 IP - 8 DP - 2016 Jul 15 TI - Sanguiin H-6, a constituent of Rubus parvifolius L., inhibits receptor activator of nuclear factor-kappaB ligand-induced osteoclastogenesis and bone resorption in vitro and prevents tumor necrosis factor-alpha-induced osteoclast formation in vivo. PG - 828-37 LID - S0944-7113(16)30033-2 [pii] LID - 10.1016/j.phymed.2016.04.002 [doi] AB - BACKGROUND: Osteoclasts are multinucleated bone-resorbing cells that differentiate in response to receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL). Enhanced osteoclastogenesis contributes to bone diseases, such as osteoporosis and rheumatoid arthritis. Rubus parvifolius L. is traditionally used as an herbal medicine for rheumatism; however, its detailed chemical composition and the molecular mechanisms responsible for its biological action have not been elucidated. PURPOSE: To investigate the mechanisms by which R. parvifolius L. extract and its major constituent sanguiin H-6, inhibit osteoclastogenesis and bone resorption. METHODS: Cell proliferation, cell differentiation, and bone resorption were detected in vitro. Inhibition of signaling pathways, marker protein expression, and protein nuclear translocation were evaluated by western blot analysis. Tumor necrosis factor-alpha (TNF-alpha)-mediated osteoclastogenesis was examined in vivo. RESULTS: R. parvifolius L. extract inhibited the bone-resorption activity of osteoclasts. In addition, sanguiin H-6 markedly inhibited RANKL-induced osteoclast differentiation and bone resorption, reduced reactive oxygen species production, and inhibited the phosphorylation of inhibitor of NF-kappaB alpha (IkappaBalpha) and p38 mitogen-activated protein kinase. Sanguiin H-6 also decreased the protein levels of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), cathepsin K, and c-Src. Moreover, sanguiin H-6 inhibited the nuclear translocation of NFATc1, c-Fos, and NF-kappaB in vitro, as well as TNF-alpha-mediated osteoclastogenesis in vivo. CONCLUSIONS: Our data revealed that R. parvifolius L. has anti-bone resorption activity and suggest that its constituent, sanguiin H-6, can potentially be used for the prevention and treatment of bone diseases associated with excessive osteoclast formation and subsequent bone destruction. CI - Copyright (c) 2016 Elsevier GmbH. All rights reserved. FAU - Sakai, Eiko AU - Sakai E AD - Division of Dental Pharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan. Electronic address: eiko-s@nagasaki-u.ac.jp. FAU - Aoki, Yuri AU - Aoki Y AD - Division of Dental Pharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan. FAU - Yoshimatsu, Masako AU - Yoshimatsu M AD - Division of Orthodontics and Dentofacial Orthopedics, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan. FAU - Nishishita, Kazuhisa AU - Nishishita K AD - Division of Dental Pharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan. FAU - Iwatake, Mayumi AU - Iwatake M AD - Division of Dental Pharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan. FAU - Fukuma, Yutaka AU - Fukuma Y AD - Division of Dental Pharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan. FAU - Okamoto, Kuniaki AU - Okamoto K AD - Division of Dental Pharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan. FAU - Tanaka, Takashi AU - Tanaka T AD - Division of Natural Product Chemistry, Department of Molecular Medicinal Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8131, Japan. FAU - Tsukuba, Takayuki AU - Tsukuba T AD - Division of Dental Pharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan. LA - eng PT - Journal Article DEP - 20160423 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 0 (Hydrolyzable Tannins) RN - 0 (Plant Extracts) RN - 0 (RANK Ligand) RN - 0 (Receptor Activator of Nuclear Factor-kappa B) RN - 0 (TNFSF11 protein, human) RN - 0 (Tumor Necrosis Factor-alpha) RN - 82978-00-5 (sanguiin H 6) SB - IM MH - Animals MH - Bone Resorption/*prevention & control MH - Cell Differentiation/drug effects MH - Cell Proliferation/drug effects MH - Hydrolyzable Tannins/*pharmacology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Osteoclasts/*drug effects MH - Osteogenesis/*drug effects MH - Plant Extracts/chemistry MH - Plant Leaves/chemistry MH - Plant Stems/chemistry MH - Protein Transport/drug effects MH - RANK Ligand/drug effects MH - Receptor Activator of Nuclear Factor-kappa B/*antagonists & inhibitors/pharmacology MH - Rubus/*chemistry MH - Tumor Necrosis Factor-alpha/*antagonists & inhibitors/pharmacology OTO - NOTNLM OT - Nuclear factor of activated T cells cytoplasmic-1 OT - Osteoclast OT - Receptor activator of nuclear factor-kappab OT - Sanguiin H-6 OT - c-Fos EDAT- 2016/06/12 06:00 MHDA- 2017/04/25 06:00 CRDT- 2016/06/12 06:00 PHST- 2015/04/10 00:00 [received] PHST- 2016/03/11 00:00 [revised] PHST- 2016/04/06 00:00 [accepted] PHST- 2016/06/12 06:00 [entrez] PHST- 2016/06/12 06:00 [pubmed] PHST- 2017/04/25 06:00 [medline] AID - S0944-7113(16)30033-2 [pii] AID - 10.1016/j.phymed.2016.04.002 [doi] PST - ppublish SO - Phytomedicine. 2016 Jul 15;23(8):828-37. doi: 10.1016/j.phymed.2016.04.002. Epub 2016 Apr 23.