title: 9-Hydroxy-6,7-dimethoxydalbergiquinol inhibits osteoclast differentiation through down-regulation of Akt, c-Fos and NFATc1.
abstract: Recently, natural plant-derived products have been recognized as one of the main sources for drug discovery and development in human disease. 9-Hydroxy-6,7-dimethoxydalbergiquinol (HDDQ) isolated from the heart wood of Dalbergia odorifera is widely used in oriental medicine, however, the pharmacological effect of HDDQ in osteoclast-associated diseases remains unknown. In this study, HDDQ dose-dependently inhibited the early stage of RANKL-mediated osteoclast differentiation in bone marrow macrophages (BMMs) without cytotoxicity. HDDQ strongly inhibited Akt phosphorylation in RANKL-stimulated BMMs and did not show any effects on p38, JNK, and IκB phosphorylation and IκB degradation. Interestingly, we found that HDDQ down-regulated the induction by RANKL of c-Fos protein by suppressing its translation. Also, ectopic overexpression of c-Fos and NFATc1 rescued the inhibition of osteoclast differentiation by HDDQ. Furthermore, the Akt/c-Fos/NFATc1-regulated expression of genes required for osteoclastogenesis, such as OSCAR and TRAP, was inhibited by HDDQ. These findings suggest that HDDQ prevents osteoclast differentiation via down-regulation of Akt, c-Fos, and NFATc1 signaling molecules, suggesting a potential therapeutic value of HDDQ for bone disorders associated with increased bone resorption.
authors.affiliation: Imaging Science-based Lung and Bone Diseases Research Center, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Oriental Medicine, Daejeon University, Daejeon 300-716, Republic of Korea.
authors.forename: Jung Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; BK21 Plus Program & Department of Smart Life-Care Convergence, Graduate School, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Yoon-Hee
authors.initials: YH
authors.lastname: Cheon
authors.affiliation: Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; BK21 Plus Program & Department of Smart Life-Care Convergence, Graduate School, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Sung Chul
authors.initials: SC
authors.lastname: Kwak
authors.affiliation: Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; BK21 Plus Program & Department of Smart Life-Care Convergence, Graduate School, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Jong Min
authors.initials: JM
authors.lastname: Baek
authors.affiliation: Standardized Material Bank for New Botanical Drugs, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Youn-Chul
authors.initials: YC
authors.lastname: Kim
authors.affiliation: Imaging Science-based Lung and Bone Diseases Research Center, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; Department of Radiology, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Kwon-Ha
authors.initials: KH
authors.lastname: Yoon
authors.affiliation: Imaging Science-based Lung and Bone Diseases Research Center, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; BK21 Plus Program & Department of Smart Life-Care Convergence, Graduate School, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; Institute for Skeletal Disease, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea. Electronic address: jmoh@wku.ac.kr.
authors.forename: Jaemin
authors.initials: J
authors.lastname: Oh
authors.affiliation: Imaging Science-based Lung and Bone Diseases Research Center, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; Institute for Skeletal Disease, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; Division of Rheumatology, Department of Internal Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea. Electronic address: ckhlms@wku.ac.kr.
authors.forename: Myeung Su
authors.initials: MS
authors.lastname: Lee
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics; D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D007527:Isoenzymes / Q000235:genetics; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008813:Mice, Inbred ICR; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: C000591712:9-hydroxy-6,7-dimethoxydalbergiquinol; D000498:Allyl Compounds; D000840:Anisoles; D007527:Isoenzymes; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C450519:Oscar protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D011956:Receptors, Cell Surface; D016173:Macrophage Colony-Stimulating Factor; D051057:Proto-Oncogene Proteins c-akt; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase
keywords: 9-Hydroxy-6,7-dimethoxydalbergiquinol; Osteoclasts; Osteoporosis; RANKL