Tunneling nanotube formation is essential for the regulation of osteoclastogenesis

Abstract

Osteoclasts are the multinucleated giant cells formed by cell fusion of mononuclear osteoclast precursors. Despite the finding of several membrane proteins involving DC-STAMP as regulatory proteins required for fusion among osteoclast precursors, cellular and molecular events concerning this process are still ambiguous. Here we identified Tunneling Nanotubes (TNTs), long intercellular bridges with small diameters, as the essential cellular structure for intercellular communication among osteoclast precursors in prior to cell fusion. Formation of TNTs was highly associated with osteoclastogenesis and it was accompanied with the significant induction of the M-Sec gene, an essential gene for TNT formation. M-Sec gene expression was significantly upregulated by RANKL-treatment in osteoclast precursor cell line. Blockage of TNT formation by Latrunclin B or by M-Sec siRNA significantly suppressed osteoclastogenesis. We have detected the rapid intercellular transport of not only the membrane phospholipids labeled with DiI but also the DC-STAMP-GFP fusion protein through TNTs formed among osteoclast precursors during osteoclastogenesis. Transportation of such regulatory molecules through TNTs would be essential for the process of the specific cell fusion among osteoclast precursors.

Emerging physiological and pathological implications of tunneling nanotubes formation between cells

“…DC-STAMP is a major regulatory protein that required for fusion osteoclast precursors. Takahashi et al (2013) identified TNTs were the essential cellular structure for intercellular communication among osteoclast precursors in prior to cell fusion. They also detected that the rapid intercellular transport of the DC-STAMP-GFP fusion protein through TNTs formed among osteoclast precursors during osteoclastogenesis (Takahashi et al, 2013).…”

“…Takahashi et al (2013) identified TNTs were the essential cellular structure for intercellular communication among osteoclast precursors in prior to cell fusion. They also detected that the rapid intercellular transport of the DC-STAMP-GFP fusion protein through TNTs formed among osteoclast precursors during osteoclastogenesis (Takahashi et al, 2013). Moreover, these intercellular bridges are essential for differentiation of mesenchymal stem cells (MSCs) into cardiomyocytes or smooth muscle cells in vivo .…”

“…Recent studies have been shown the importance role of TNTs in mechanical and signaling processes during embryonic patterning and development (Caneparo et al, 2011). Interestingly, it have also been reported TNTs can contribute in cellular differentiation and reprogramming by providing a highway to transfer cellular components from one cell to a target cell (Koyanagi et al, 2005;Rolf et al, 2012;Takahashi et al, 2013). They are also important in pathological situations.…”

Trophic Effects of Mesenchymal Stem Cells in Tissue Regeneration

“…158 Recently, MNTs have been observed between MSCs and vascular smooth muscle cells (VSMCs), which promoted the proliferation but not differentiation of MSCs by transfer of mitochondria from VSMCs into MSCs, 178 as well as between MSCs and osteoclast precursors, which was found to be essential for osteoclastogenesis. 179 Overall, MNTs are novel candidates to explain how direct cell-to-cell communication occurs and play an important role in many (patho)physiological processes by transporting molecular signals and cell organelles from one cell to another. 180 We propose that communication through nanotubes could be an additional mechanism by which MSCs exert their positive effect in tissue regeneration.…”

Membrane nanotubes: Novel communication between distant cells

“…Recently, MNTs observed between MSCs and vascular smooth muscle cells promoted the proliferation but not differentiation of MSCs by transfer of mitochondria [23], and MNTs between osteoclast precursors were found essential for osteoclastogenesis [33]. MNTs also exist between malignant tumor cells of mesothelioma and lung cancer and might play a critical role in tumor formation and development [7].…”