title: The 4-1BB ligand and 4-1BB expressed on osteoclast precursors enhance RANKL-induced osteoclastogenesis via bi-directional signaling.
abstract: The 4-1BB is a costimulatory molecule similar to the receptor activator of NF-kappaB ligand (RANKL), both of which are key factors for the differentiation of osteoclasts and are expressed mainly by activated T cells. The 4-1BB shares common signaling pathways with RANK, suggesting a potential role in osteoclastogenesis. In this study, the role of 4-1BB and 4-1BB ligand (4-1BBL) in osteoclastogenesis was investigated using 4-1BB(-/-) and 4-1BB(+/+) mice. Osteoclast precursors normally express 4-1BB and 4-1BBL after exposure to RANKL, which was confirmed by semi-quantitative RT-PCR and flow cytometry. The 4-1BB(-/- )mice had a slightly increased bone mass accompanied by a reduced osteoclastogenic ability of 4-1BB(-/-) bone marrow-derived macrophages (BMM) ex vivo. In addition, 4-1BB(-/-) BMM demonstrated hypophosphorylation of JNK and p38 and decreased induction of c-Fos in response to RANKL stimulation. Retroviral transduction of wild-type as well as partial-length 4-1BB, which lacks TNF receptor-associated factor 2-binding sites for signaling, restored the osteoclastogenic ability of 4-1BB(-/-) BMM. Furthermore, both recombinant 4-1BB and 4-1BBL enhanced RANKL-induced osteoclastogenesis by 4-1BB(+/+) BMM and the induction of c-Fos and NFATc1.Together, these results indicate that 4-1BBL and 4-1BB expressed on osteoclast precursors enhance RANKL-induced osteoclastogenesis via bi-directional signaling, findings that may delineate the complex nature of the 4-1BBL and 4-1BB interaction.
authors.affiliation: Department of Oromaxillofacial Infection and Immunity, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea.
authors.forename: Jihyun
authors.initials: J
authors.lastname: Yang
authors.forename: Ok Jin
authors.initials: OJ
authors.lastname: Park
authors.forename: Yeon Ju
authors.initials: YJ
authors.lastname: Lee
authors.forename: Hong-Moon
authors.initials: HM
authors.lastname: Jung
authors.forename: Kyung Mi
authors.initials: KM
authors.lastname: Woo
authors.forename: Youngnim
authors.initials: Y
authors.lastname: Choi
mesh_terms: D053330:4-1BB Ligand / Q000235:genetics / Q000502:physiology*; D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000235:genetics; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D053245:RANK Ligand / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013977:Tibia / Q000033:anatomy & histology; D014161:Transduction, Genetic; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D053330:4-1BB Ligand; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D011994:Recombinant Proteins; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D016173:Macrophage Colony-Stimulating Factor; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; D000135:Acid Phosphatase