title: Genipin inhibits RANKL-induced osteoclast differentiation through proteasome-mediated degradation of c-Fos protein and suppression of NF-κB activation.
abstract: People over the age of 50 are at risk of osteoporotic fracture, which may lead to increased morbidity and mortality. Osteoclasts are responsible for bone resorption in bone-related disorders. Genipin is a well-known geniposide aglycon derived from Gardenia jasminoides, which has long been used in oriental medicine for controlling diverse conditions such as inflammation and infection. We aimed to evaluate the effects of genipin on RANKL-induced osteoclast differentiation and its mechanism of action. Genipin dose-dependently inhibited early stage RANKL-induced osteoclast differentiation in bone marrow macrophages (BMMs) during culture. Genipin inhibited RANKL-induced IκB degradation and suppressed the mRNA expression of osteoclastic markers such as NFATc1, TRAP, and OSCAR in RANKL-treated BMMs, but did not affect c-Fos mRNA expression. Interestingly, genipin markedly inhibited c-Fos protein expression in BMMs, which was reversed in the presence of the proteosome inhibitor MG-132. Furthermore, genipin inhibited RANKL-mediated osteoclast differentiation, which was also rescued by overexpression of c-Fos and NFATc1 in BMMs. Taken together, our findings indicate that genipin down-regulated RANKL-induced osteoclast differentiation through inhibition of c-Fos protein proteolysis as well as inhibition of IκB degradation. Our findings indicate that genipin could be a useful drug candidate that lacks toxic side effects for the treatment of osteoporosis.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, School of Medicine, Wonkwang University, Korea.
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Lee
authors.forename: Sung-Chul
authors.initials: SC
authors.lastname: Kwak
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Hyun Mee
authors.initials: HM
authors.lastname: Oh
authors.forename: Mun Chual
authors.initials: MC
authors.lastname: Rho
authors.forename: Kwon-Ha
authors.initials: KH
authors.lastname: Yoon
authors.forename: Wan-Hee
authors.initials: WH
authors.lastname: Yoo
authors.forename: Myeung Su
authors.initials: MS
authors.lastname: Lee
authors.forename: Jaemin
authors.initials: J
authors.lastname: Oh
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D032062:Gardenia; D039823:Iridoids / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects; D010024:Osteoporosis / Q000188:drug therapy; D008517:Phytotherapy; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D059748:Proteolysis / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D053245:RANK Ligand / Q000502:physiology
chemical_list: D039823:Iridoids; D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; C007834:genipin; D046988:Proteasome Endopeptidase Complex