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Dynamic visualization of RANKL and Th17-mediated osteoclast function
Junichi Kikuta, … , Ronald N. Germain, Masaru Ishii
Junichi Kikuta, … , Ronald N. Germain, Masaru Ishii
Published January 16, 2013
Citation Information: J Clin Invest. 2013;123(2):866-873. https://doi.org/10.1172/JCI65054.
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Technical Advance Bone Biology

Dynamic visualization of RANKL and Th17-mediated osteoclast function

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Abstract

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.

Authors

Junichi Kikuta, Yoh Wada, Toshiyuki Kowada, Ze Wang, Ge-Hong Sun-Wada, Issei Nishiyama, Shin Mizukami, Nobuhiko Maiya, Hisataka Yasuda, Atsushi Kumanogoh, Kazuya Kikuchi, Ronald N. Germain, Masaru Ishii

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Figure 6

Regulation of mature osteoclast function by RANKL expressed on Th17.

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Regulation of mature osteoclast function by RANKL expressed on Th17.
(A)...
(A) Mature osteoclasts (green/red/yellow) either alone or in conjugate with Th17 (magenta); corresponding CDIs were determined (see details in Figure 1D). Scale bars: 5 μm. (B) Histogram of CDIs of mature osteoclasts conjugated with Th17 (black) and under control conditions (gray, same as in Figure 1H). (C) Summary of the CDIs of mature osteoclasts alone or conjugated with Th1 or Th17 (n = 10 for nonconjugated [Non], n = 6 for Th1-conjugated [Th1], and n = 12 for Th17-conjugated [Th17]). (D) A representative image showing a migrating Th17 contacting a mature osteoclast. Green, mature osteoclast; red, Th17. Scale bar: 5 μm. (E) Change in osteoclast motility associated with Th17 contact. The CDIs before (left) and after (right) conjugation with Th17 are depicted. Magenta, Th17. Scale bars: 5 μm. (F) Summary of CDI changes corresponding to Th17 conjugation (n = 4). Moving (high CDI) osteoclasts underwent transition into static (low CDI) states 20 minutes after conjugation with Th17. (G) Representative images of live bone imaging of wild-type mice treated with BAp-E. In vitro–differentiated Th1 (left) or Th17 (right) were labeled with CMTPX (red) and then transferred as independent. Fluorescent signals from high H+ concentration are in green. Blue, bone surface. Scale bar: 10 μm. (H) The ratio of the number of Th1 or Th17 attached to the BAp-E divided by the total number of Th1 or Th17 (n = 4). Each experiment was performed independently at least 3 times.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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