title: Natural polyamines inhibit the migration of preosteoclasts by attenuating Ca2+-PYK2-Src-NFATc1 signaling pathways.
abstract: Natural polyamines have numerous biological activities. Several studies have reported their beneficial role in bone metabolism, but their mode of action is not fully understood. Bone diseases such as osteoporosis, which is characterized by impaired bone structure and low bone mass, are caused by an increased number of osteoclasts and/or overactivation of osteoclastogenesis. Osteoclast differentiation is a multi-complex procedure involving the following sequential steps: differentiation-migration-fusion-resorption. In this study, we found that putrescine, spermidine or spermine inhibited the RANKL-mediated migration of preosteoclasts. Furthermore, the RANKL-mediated activation of the Src-PYK2 signaling axis and of transcription factors such as NF-κB and NFATc1 was prevented by each polyamine. Anti-osteoclastogenic and anti-migration activities of polyamines were confirmed by evaluating their potential to downregulate the mRNA expression levels of osteoclastogenesis-related genes such as OSCAR, TRAP, cathepsin K and c-Src, and genes related to fusion and/or migration of preosteoclasts. Moreover, ATP-mediated elevation of cytosolic free Ca(2+) concentration ([Ca(2+)]i) was strongly inhibited by each polyamine, indicating the involvement of [Ca(2+)]i in the anti-fusion activities of polyamines. In conclusion, polyamines could exhibit anti-osteoclastogenic activity by inhibiting the migration of preosteoclasts via the Ca(2+)-PYK2-Src-NFATc1 signaling axis.
authors.affiliation: Research Institute of Basic Science, Sunchon National University, Suncheon, 540-742, Republic of Korea.
authors.forename: Jeong-Tae
authors.initials: JT
authors.lastname: Yeon
authors.forename: Byung Jun
authors.initials: BJ
authors.lastname: Ryu
authors.forename: Sik-Won
authors.initials: SW
authors.lastname: Choi
authors.forename: Jin-Chul
authors.initials: JC
authors.lastname: Heo
authors.forename: Kwang-Jin
authors.initials: KJ
authors.lastname: Kim
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Son
authors.forename: Seong Hwan
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption; D002118:Calcium / Q000378:metabolism*; D002454:Cell Differentiation; D002465:Cell Movement; D004305:Dose-Response Relationship, Drug; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D011073:Polyamines / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction; D013096:Spermine / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D011073:Polyamines; D053245:RANK Ligand; D013096:Spermine; D000255:Adenosine Triphosphate; D051418:Focal Adhesion Kinase 2; D002118:Calcium