Regulators of osteoclast differentiation and cell-cell fusion.
Osteoclasts are multinuclear giant cells derived from osteoclast/macrophage/dendritic       cell common progenitor cells. The most characteristic feature of osteoclasts is       multinucleation resulting from cell-cell fusion of mononuclear osteoclasts. Osteoclast       cell-cell fusion is considered essential for re-organization of the cytoskeleton, such as the       actin-ring and ruffled boarder to seal the resorbing area and to secret protons, respectively,       to resorb bone; the fusion process is thus critical for osteoclast function. Various       molecules, such as E-cadherin and macrophage fusion receptor (MFR), have been identified as       regulators of osteoclast or macrophage cell-cell fusion. Laboratory production of osteoclasts       used to be performed in a co-culture of osteoclast progenitors with osteoblastic cells, but       recent advances in the identification of nuclear factor of kappa B ligand (RANKL) enabled the       isolation of osteoclast-specific molecules involving osteoclast cell-cell fusion and       differentiation regulators from purified osteoclast mRNA, since osteoclasts can be formed       without osteoblasts. The essential cell-cell fusion regulator, dendritic cell-specific       transmembrane protein (DC-STAMP), was isolated by a cDNA subtractive screen between       mononuclear macrophages and RANKL-induced multinuclear osteoclasts. The cell-cell fusion of       osteoclasts and foreign body giant cells (FBGCs) was completely abrogated in       DC-STAMP-deficient mice in vivo and in vitro. Bone resorbing activity was significantly       reduced but was still detected in DC-STAMP-deficient osteoclasts. DC-STAMP expression is       positively regulated by two transcriptional factors: nuclear factor of activated T cells 1       (NFATc1) and c-Fos, both of which are essential for osteoclast differentiation. Furthermore, a       novel osteoclastogenesis-regulating pathway involving two transcriptional repressors [B cell       lymphoma 6 (Bcl6) and B lymphocyte-induced maturation protein 1 (Blimp1)] under RANKL       stimulation has been discovered. The expression of osteoclastic genes such as DC-STAMP,       NFATc1, and Cathepsin K, as well as osteoclast differentiation, was inhibited by Bcl6.       Bcl6-deficient mice showed enhanced osteoclastogenesis and reduced bone mass, whereas       osteoclast-specific Blimp1-conditional knockout mice showed elevated Bcl6 expression,       osteoclastic gene expression, and osteoclast differentiation and increased bone mass. In this       review, recent advances in our understanding of the regulators of osteoclast differentiation       and cell-cell fusion are discussed.
Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan. miyamoto@z5.keio.jp
Takeshi
T
Miyamoto
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D002459:Cell Fusion; D006706:Homeostasis; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism / Q000502:physiology*; D053245:RANK Ligand / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C501589:DCSTAMP protein, human; D008565:Membrane Proteins; D053245:RANK Ligand