Cell-surface phosphatidylserine regulates osteoclast precursor fusion

Santosh K. Verma, Evgenia Leikina, Kamran Melikov, Claudia Gebert, Vardit Kram, Marian F. Young, Berna Uygur, Leonid V. Chernomordik
2017 Journal of Biological Chemistry  
Edited by Xiao-Fan Wang Bone-resorbing multinucleated osteoclasts that play a central role in the maintenance and repair of our bones are formed from bone marrow myeloid progenitor cells by a complex differentiation process that culminates in fusion of mononuclear osteoclast precursors. In this study, we uncoupled the cell fusion step from both pre-fusion stages of osteoclastogenic differentiation and the post-fusion expansion of the nascent fusion connections. We accumulated ready-to-fuse
more » ... in the presence of the fusion inhibitor lysophosphatidylcholine and then removed the inhibitor to study synchronized cell fusion. We found that osteoclast fusion required the dendrocyte-expressed seven transmembrane protein (DC-STAMP)-dependent non-apoptotic exposure of phosphatidylserine at the surface of fusion-committed cells. Fusion also depended on extracellular annexins, phosphatidylserine-binding proteins, which, along with annexin-binding protein S100A4, regulated fusogenic activity of syncytin 1. Thus, in contrast to fusion processes mediated by a single protein, such as epithelial cell fusion in Caenorhabditis elegans, the cell fusion step in osteoclastogenesis is controlled by phosphatidylserine-regulated activity of several proteins. 2 The abbreviations used are: LPC, lysophosphatidylcholine; Anx, annexin; BMC, bone marrow cell; HM, human monocyte; M-CSF, macrophage colony-stimulating factor; PS, phosphatidylserine; RANK, receptor activator of nuclear factor-B; RANKL, receptor activator of nuclear factor-B ligand; OCP, osteoclast precursor cell; TRAP, tartrate-resistant acidic phosphatase; MEM-␣, minimal essential medium-␣; CDF, cumulative distribution function; DiI, 1,1Јdioctadecyl-3,3,3Ј,3Ј-tetramethylindocarbocyanine perchlorate. cro ARTICLE 254
doi:10.1074/jbc.m117.809681 pmid:29101233 fatcat:vacpvuqt3rfn5put5ovhrvg4ee