title: Oleanolic acid acetate inhibits osteoclast differentiation by downregulating PLCγ2-Ca(2+)-NFATc1 signaling, and suppresses bone loss in mice.
abstract: Owing to their potential pharmacological activities in human disease, natural plant-derived compounds have recently become the focus of increased research interest. In this study, we first isolated oleanolic acid acetate (OAA), a triterpenoid compound, from Vigna angularis (azuki bean) to discover anti-bone resorptive agents. Many studies have identified and described the various medicinal effects of V. angularis extract. However, the pharmacological effect of OAA-derived V. angularis extract, particularly the effect on osteoclastogenesis, is not known. Therefore, we investigated the effect and mechanism of OAA in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. OAA inhibited RANKL-induced osteoclast differentiation in bone marrow macrophages (BMMs) without any evidence of cytotoxicity. Interestingly, OAA significantly inhibited Btk phosphorylation, phospholipase Cγ2 (PLCγ2) phosphorylation, calcium ion (Ca(2+)) oscillation, and nuclear factor of activated T cell c1 (NFATc1) expression in RANKL-stimulated BMMs, but did not affect RANKL-induced mitogen-activated protein kinase. OAA also inhibited the bone-resorbing activity of mature osteoclasts. Furthermore, mice treated with OAA demonstrated marked attenuation of lipopolysaccharide-induced bone erosion based on micro-computed tomography and histologic analysis of femurs. Taken together, the results suggested that OAA inhibited RANKL-mediated osteoclastogenesis via PLCγ2-Ca(2+)-NFATc1 signaling in vitro and suppressed inflammatory bone loss in vivo.
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 Anatomy, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Yoon-Hee
authors.initials: YH
authors.lastname: Cheon
authors.affiliation: Bioindustrial Process Research Center, Bio-Materials Research Institute, Korea Research Institute of Bioscience and Biotechnology, Jeongeup, Jeonbuk 580-185, Republic of Korea.
authors.forename: Hyun Mee
authors.initials: HM
authors.lastname: Oh
authors.affiliation: Bioindustrial Process Research Center, Bio-Materials Research Institute, Korea Research Institute of Bioscience and Biotechnology, Jeongeup, Jeonbuk 580-185, Republic of Korea.
authors.forename: Mun Chual
authors.initials: MC
authors.lastname: Rho
authors.affiliation: Department of Oral Physiology, School of Dentistry, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Munkhsoyol
authors.initials: M
authors.lastname: Erkhembaatar
authors.affiliation: Department of Oral Physiology, School of Dentistry, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; Institute for Skeletal Disease, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Min Seuk
authors.initials: MS
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; Institute for Skeletal Disease, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Jeong Joong
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Min Kyu
authors.initials: MK
authors.lastname: Choi
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; 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
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; 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
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051966:Phospholipase C gamma / Q000378:metabolism*; D053245:RANK Ligand / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D008070:Lipopolysaccharides; D050778:NFATC Transcription Factors; D053245:RANK Ligand; D009828:Oleanolic Acid; D051966:Phospholipase C gamma; D002118:Calcium
keywords: Calcium oscillation; NFATc1; Oleanolic acid acetate; Osteoclast; PLCγ2