title: Momordin I, an inhibitor of AP-1, suppressed osteoclastogenesis through inhibition of NF-kappaB and AP-1 and also reduced osteoclast activity and survival.
abstract: Osteoclasts originating from hematopoietic precursor cells differentiate into multinucleated cells through multiple steps. The essential roles of NF-kappaB and AP-1 in osteoclast differentiation have been clearly demonstrated in numerous studies. c-Fos, a component of AP-1 transcription factor, plays a key role in osteoclast differentiation. Recently, we found a strong inhibitor of AP-1 transcriptional activity, named momordin I, based on the structure of oleanolic acid glycosides and originally isolated from Ampelopsis radix. So, we hypothesized that momordin I might be able to regulate osteoclast formation, activity, and survival. Here, we report the ability of momordin I to suppress osteoclastogenesis in a co-cultured system and a RANKL-induced osteoclast precursor system. Momordin I remarkably inhibited the activation of NF-kappaB as well as AP-1 in RANKL-induced RAW264.7 cells, in which momordin I appeared to target IkappaB degradation and c-Fos expression, respectively, but not MAPK signaling pathways. The ability of momordin I to change the ratio of RANKL and OPG in primary osteoblasts was partially responsible for the reduction of osteoclast formation. Furthermore, pit formation on dentin slices was suppressed by momordin I with stimulating actin ring disruption. Our results also showed that momordin I highly shortened osteoclast lifespan and induced osteoclast apoptosis. In conclusion, the present results demonstrate for the first time that momordin I is a potent inhibitor of osteoclast differentiation via the reduction of NF-kappaB and AP-1, and also suppresses osteoclast function and survival.
authors.affiliation: Department of Chemistry (NS60), Seoul National University, Shinlim-Dong san 56-1, Seoul 151-747, Republic of Korea.
authors.forename: Yun Ha
authors.initials: YH
authors.lastname: Hwang
authors.forename: Jung Wook
authors.initials: JW
authors.lastname: Lee
authors.forename: Eun-Ryeong
authors.initials: ER
authors.lastname: Hahm
authors.forename: Kyung Chae
authors.initials: KC
authors.lastname: Jung
authors.forename: Ju Hyung
authors.initials: JH
authors.lastname: Lee
authors.forename: Chi Hoon
authors.initials: CH
authors.lastname: Park
authors.forename: Ho Sung
authors.initials: HS
authors.lastname: Rhee
authors.forename: Je Man
authors.initials: JM
authors.lastname: Ryu
authors.forename: Hyun-Kyung
authors.initials: HK
authors.lastname: Kim
authors.forename: Chul-Hak
authors.initials: CH
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000378:metabolism*; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D018808:Transcription Factor AP-1; C408362:momordin I (Oleanolic Acid); D009828:Oleanolic Acid