PMID- 25978953 OWN - NLM STAT- MEDLINE DCOM- 20160308 LR - 20150616 IS - 1872-7573 (Electronic) IS - 0378-8741 (Linking) VI - 170 DP - 2015 Jul 21 TI - An 8-O-4' norlignan exerts oestrogen-like actions in osteoblastic cells via rapid nongenomic ER signaling pathway. PG - 39-49 LID - S0378-8741(15)00337-2 [pii] LID - 10.1016/j.jep.2015.05.012 [doi] AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sambucus williamsii Hance (SWH), which belongs to the Caprifoliaceae family distributed in various regions of China, Korea and Japan, has been used as a folk medicine for treatment of bone and joint diseases in China for thousands of years. In previous studies, SWH was shown to possess anti-osteoporosis, healing fracture, anti-inflammatory and analgesic activities. Our previous studies showed that SWH extract effectively suppressed ovariectomy-induced increase in bone turnover and improved bone mineral density and bone biomechanical strength in rats as well as in mice. An 8-O-4' norlignan, (7R,8S)-1-(4-hydroxy-3-methoxyphenyl)-2-[4-(3-hydroxypropyl)-2-methoxyphenoxy]-1,3-propanediol (PPD) was previously isolated and identified as the bioactive ingredient in SWH. The present study aimed to characterize the bone protective effects as well as its mechanism of actions in osteoblasts. MATERIALS AND METHODS: Bone protective actions of PPD on different cells were determined by proliferation assay, alkaline phosphatase (ALP) activity assay, calcium deposition as well as real-time reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, estrogen receptor (ER) antagonist ICI182,780 and mitogen-activated protein kinase kinase (MEK) inhibitor U0126 blocking assays, competitive ER radioligand binding assay, ERE-dependent luciferase reporter assay and immunoblotting were used to determine if PPD activated ER and if the effects of PPD on osteoblastic functions were ER dependent. RESULTS: PPD exerted anabolic effects in osteoblasts and its effects were abolished by co-incubation with ICI182,780 or U0126. PPD induced mRNA expressions of Runx2, ALP, osteocalcin, and increased the ratio of osteoprotegerin/receptor activator of nuclear factor kappaB (OPG/RANKL). PPD failed to bind to either ERalpha or ERbeta and did not activate ERE-luciferase activity via ER. PPD induced the phosphorylation of extracellular regulated kinases (ERK) and its effect was completely abolished by U0126. It also induced the phosphorylation of ERalpha at serine 118. CONCLUSION: These data show that PPD is a bioactive compound in SWH that exerts oestrogen-like actions in osteoblast-like cells via ligand-independent, estrogen response element (ERE)-independent and mitogen-activated protein (MAP) Kinase-mediated rapid nongenomic ER signaling pathway. CI - Copyright (c) 2015 Elsevier Ireland Ltd. All rights reserved. FAU - Xiao, Hui-Hui AU - Xiao HH AD - State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen Research Institute of The Hong Kong Polytechnic University, Shenzhen 518057, PR China; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China. FAU - Gao, Quan-Gui AU - Gao QG AD - Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China. FAU - Ho, Ming-Xian AU - Ho MX AD - Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China. FAU - Zhang, Yan AU - Zhang Y AD - Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China; Center for Systems Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai 200093, PR China. FAU - Wong, Ka-Chun AU - Wong KC AD - Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China. FAU - Dai, Yi AU - Dai Y AD - Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China. FAU - Yao, Xin-Sheng AU - Yao XS AD - Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China. Electronic address: tyaoxs@jnu.edu.cn. FAU - Wong, Man-Sau AU - Wong MS AD - State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen Research Institute of The Hong Kong Polytechnic University, Shenzhen 518057, PR China; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China. Electronic address: bcmswong@polyu.edu.hk. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150512 PL - Ireland TA - J Ethnopharmacol JT - Journal of ethnopharmacology JID - 7903310 RN - 0 ((7R,8S)-1-(4-hydroxy-3-methoxyphenyl)-2-(4-(3-hydroxypropyl)-2-methoxyphenoxy)-1,3-propanediol) RN - 0 (Estrogen Receptor alpha) RN - 0 (Estrogen Receptor beta) RN - 0 (Lignans) RN - 0 (Phytoestrogens) SB - IM MH - Animals MH - Bone and Bones/drug effects/metabolism MH - Cell Line MH - Estrogen Receptor alpha/metabolism MH - Estrogen Receptor beta/metabolism MH - Lignans/chemistry/isolation & purification/*pharmacology MH - MAP Kinase Signaling System/drug effects MH - Mice MH - Osteoblasts/*drug effects MH - Phosphorylation/drug effects MH - Phytoestrogens/chemistry/isolation & purification/*pharmacology MH - Rats MH - Reverse Transcriptase Polymerase Chain Reaction MH - Sambucus/*chemistry MH - Signal Transduction/drug effects OTO - NOTNLM OT - 8-O-4' lignan OT - MAP kinase signaling pathway OT - Osteoblast OT - Phytoestrogen OT - Sambucus willamsii Hance EDAT- 2015/05/17 06:00 MHDA- 2016/03/10 06:00 CRDT- 2015/05/17 06:00 PHST- 2014/12/23 00:00 [received] PHST- 2015/04/27 00:00 [revised] PHST- 2015/05/04 00:00 [accepted] PHST- 2015/05/17 06:00 [entrez] PHST- 2015/05/17 06:00 [pubmed] PHST- 2016/03/10 06:00 [medline] AID - S0378-8741(15)00337-2 [pii] AID - 10.1016/j.jep.2015.05.012 [doi] PST - ppublish SO - J Ethnopharmacol. 2015 Jul 21;170:39-49. doi: 10.1016/j.jep.2015.05.012. Epub 2015 May 12.