Dynamic visualization of RANKL and Th17-mediated osteoclast function

• Published in: The Journal of clinical investigation Vol. 123; no. 2; p. 866
• Main Authors: Kikuta, Junichi, Wada, Yoh, Kowada, Toshiyuki, Wang, Ze, Sun-Wada, Ge-Hong, Nishiyama, Issei, Mizukami, Shin, Maiya, Nobuhiko, Yasuda, Hisataka, Kumanogoh, Atsushi, Kikuchi, Kazuya, Germain, Ronald N., Ishii, Masaru
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.02.2013
• Subjects: Animals; Biomedical research; Bone Resorption - etiology; Bone Resorption - pathology; Bone Resorption - physiopathology; Bones; Cell Communication - physiology; Cell Differentiation - drug effects; Cell Differentiation - physiology; Mice; Mice, Transgenic; Microscopy; Microscopy, Fluorescence, Multiphoton; Motility; Osteoclasts (Biology); Osteoclasts - drug effects; Osteoclasts - physiology; Physiological aspects; Proteins; RANK Ligand - administration & dosage; RANK Ligand - genetics; RANK Ligand - physiology; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Recombinant Proteins - administration & dosage; Recombinant Proteins - genetics; Stem cells; Technical Advance; Th17 Cells - physiology; Tumor necrosis factor; Vacuolar Proton-Translocating ATPases - genetics; Vacuolar Proton-Translocating ATPases - metabolism; United States; Japan
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI65054

Osteoclasts are bone resorbing, multinucleate cells that differentiate from mononuclear macrophage/monocyte-lineage hematopoietic precursor cells. Although previous studies have revealed important molecular signals, how the bone resorptive functions of such cells are controlled in vivo remains less well characterized. Here, we visualized fluorescently labeled mature osteoclasts in intact mouse bone tissues using intravital multiphoton microscopy. Within this mature population, we observed cells with distinct motility behaviors and function, with the relative proportion of static - bone resorptive (R) to moving - nonresorptive (N) varying in accordance with the pathophysiological conditions of the bone. We also found that rapid application of the osteoclast-activation factor RANKL converted many N osteoclasts to R, suggesting a novel point of action in RANKL-mediated control of mature osteoclast function. Furthermore, we showed that Th17 cells, a subset of RANKL-expressing CD4+ T cells, could induce rapid N-to-R conversion of mature osteoclasts via cell-cell contact. These findings provide new insights into the activities of mature osteoclasts in situ and identify actions of RANKL-expressing Th17 cells in inflammatory bone destruction.