title: Dynein light chain LC8 inhibits osteoclast differentiation and prevents bone loss in mice.
abstract: NF-κB is one of the key transcription factors activated by receptor activator of NF-κB ligand (RANKL) during osteoclast differentiation. The 8-kDa dynein L chain (LC8) was previously identified as a novel NF-κB regulator. However, its physiological role as an NF-κB inhibitor remains elusive. In this study, we showed the inhibitory role of LC8 in RANKL-induced osteoclastogenesis and signaling pathways and its protective role in osteolytic animal models. LC8 suppressed RANKL-induced osteoclast differentiation, actin ring formation, and osteoclastic bone resorption. LC8 inhibited RANKL-induced phosphorylation and subsequent degradation of IκBα, the expression of c-Fos, and the consequent activation of NFATc1, which is a pivotal determinant of osteoclastogenesis. LC8 also inhibited RANKL-induced activation of JNK and ERK. LC8-transgenic mice exhibited a mild osteopetrotic phenotype. Moreover, LC8 inhibited inflammation-induced bone erosion and protected against ovariectomy-induced bone loss in mice. Thus, our results suggest that LC8 inhibits osteoclast differentiation by regulating NF-κB and MAPK pathways and provide the molecular basis of a new strategy for treating osteoporosis and other bone diseases.
authors.affiliation: Division of Life and Pharmaceutical Sciences, Department of Life Sciences, and Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Hyeryeon
authors.initials: H
authors.lastname: Kim
authors.forename: Seungha
authors.initials: S
authors.lastname: Hyeon
authors.forename: Hojin
authors.initials: H
authors.lastname: Kim
authors.forename: Yoohee
authors.initials: Y
authors.lastname: Yang
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Huh
authors.forename: Doo Ri
authors.initials: DR
authors.lastname: Park
authors.forename: Hyojung
authors.initials: H
authors.lastname: Lee
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Seo
authors.forename: Han-Sung
authors.initials: HS
authors.lastname: Kim
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Woojin
authors.initials: W
authors.lastname: Jeong
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D001862:Bone Resorption / Q000517:prevention & control*; D002454:Cell Differentiation; D056445:Cytoplasmic Dyneins / Q000235:genetics / Q000502:physiology* / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000502:physiology; D016762:Genes, fos; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D010010:Osteoclasts / Q000473:pathology*; D010014:Osteolysis / Q000503:physiopathology / Q000517:prevention & control*; D010022:Osteopetrosis / Q000235:genetics; D015663:Osteoporosis, Postmenopausal / Q000503:physiopathology / Q000517:prevention & control; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D053245:RANK Ligand / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000502:physiology / Q000633:toxicity; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000199:Actins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C000606204:NFKBIA protein, human; C494005:Nfatc1 protein, mouse; C000606205:Nfkbia protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D011993:Recombinant Fusion Proteins; C505689:Tnfsf11 protein, mouse; D000072000:NF-KappaB Inhibitor alpha; C427758:DYNLL1 protein, human; D056445:Cytoplasmic Dyneins