Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal-replacement therapy at 20 ml per kilogram per hour. (ClinicalTrials.gov number, NCT00076219.)

The macrophage fusion receptor (MFR), also called P84/BIT/SIRP␣/SHPS-1, is a transmembrane glycoprotein that belongs to the superfamily of immunoglobulins. Previously, we showed that MFR expression is highly induced at the onset of fusion in macrophages, and that MFR appears to play a role in macrophagemacrophage adhesion/fusion leading to multinucleation. The recent finding that IAP/CD47 acts as a ligand for MFR led us to hypothesize that it interacts with CD47 at the onset of cell-cell fusion. CD47 is a transmembrane glycoprotein, which, like MFR, belongs to the superfamily of immunoglobulins. We show that macrophages express the hemopoietic form of CD47, the expression of which is induced at the onset of fusion, but to a lower level than MFR. A glutathione S-transferase CD47 fusion protein engineered to contain the extracellular domain of CD47, binds macrophages, associates with MFR, and prevents multinucleation. CD47 and MFR associate via their amino-terminal immunoglobulin variable domain. Of the nine monoclonal antibodies raised against the extracellular domain of CD47, three block fusion, as well as MFR-CD47 interaction, whereas the others have no effect. Together, these data suggest that CD47 is involved in macrophage multinucleation by virtue of interacting with MFR during adhesion/fusion.Osteoclasts and giant cells are characterized by multinucleation and a powerful ability to resorb the substrate onto which they adhere. Although osteoclasts and giant cells play an important role in bone remodeling and immune defense, respectively, they are also associated with osteoporosis, granulomatous diseases, and tumors.Multinucleation appears to endow macrophages with the capacity to digest and resorb extracellular infectious agents, foreign material, and other components that are too large to be internalized, such as bone. This resorption occurs in an "extracellular lysosomal compartment" sealed off between the multinucleated cell and its target substrate (reviewed in Ref.1). The plasma membrane that faces that extracellular domain is highly ruffled and specialized. Multinucleation gives macrophages added resorptive capacity, in part by making available a large excess of plasma membrane.Understanding the mechanism by which macrophages differentiate into osteoclasts and multinucleated giant cells is of extreme importance. One of the key steps in the differentiation of osteoclasts and giant cells is the fusion mechanism of their mononucleated precursor cells. It is assumed that both osteoclasts and giant cells originate from the fusion of mononuclear phagocytes. Despite the pathophysiological importance of these cells, the mechanism by which their mononucleated precursors fuse remains poorly understood. Indeed, cell-cell fusion itself, whether it concerns that of sperm cells with oocytes in fertilization or myoblasts with myoblasts in muscle development, has not been investigated thoroughly. It is proposed that cell-cell fusion involves a set of proteins similar to those used by viruses to fuse with host cells be...

We had previously identified a macrophage surface protein whose expression is highly induced, transient, and specific, as it is restricted to actively fusing macrophages in vitro and in vivo. This protein is recognized by monoclonal antibodies that block macrophage fusion. We have now purified this protein and cloned its corresponding cDNA. This protein belongs to the superfamily of immunoglobulins and is similar to immune antigen receptors such as the T-cell receptor, B-cell receptor, and viral receptors such as CD4. We have therefore named this protein macrophage fusion receptor (MFR). We show that the extracellular domain of MFR prevents fusion of macrophages in vitro and therefore propose that MFR belongs to the fusion machinery of macrophages. MFR is identical to SHPS-1 and BIT and is a homologue of P84, SIRP␣, and MyD-1, all of which have been recently cloned and implicated in cell signaling and cell-cell interaction events.Membrane fusion is a ubiquitous event that occurs in a wide range of cell biological processes. While intracellular membrane fusion mediating interorganelle traffic is well studied, much less is known about cell-cell fusion mediating sperm cell-oocyte, myoblast-myoblast, and macrophage-macrophage fusion. These fusion events are required for fertilization, muscle, and osteoclast development, respectively. In the case of mononuclear phagocytes, fusion is associated not only with the differentiation of osteoclasts, cells which play a key role in the pathogenesis of osteoporosis, but also with the formation of giant cells that are present in chronic inflammatory reactions and in tumors. Despite the biological and pathophysiological importance of intercellular fusion events, the actual molecular mechanisms of cell-cell fusion are still unclear.

Cells of the mononuclear phagocyte lineage have the capability to adhere to and fuse with each other and to differentiate into osteoclasts and giant cells. To investigate the macrophage adhesion/fusion mechanism, we focused our attention on CD44, a surface glycoprotein known to play a role in hematopoietic cell–cell adhesion. We report that CD44 expression by macrophages is highly and transiently induced by fusogenic conditions both in vitro and in vivo. We show that CD44 ligands, hyaluronic acid, chondroitin sulfates, and osteopontin prevent macrophage multinucleation. In addition, we report that the recombinant extracellular domain of CD44 binds fusing macrophages and prevents multinucleation in vitro. These data suggest that CD44 may control the mononucleated status of macrophages in tissues by virtue of mediating cell–cell interaction.