Meltrin-α, a Fusion Protein Involved in Multinucleated Giant Cell and Osteoclast Formation

Abstract

The formation of multinucleated cells such as myotubes, macrophage-derived giant cells (MGC), and osteoclasts is the result of cell-cell fusion of mononuclear precursors. Meltrin-alpha, -beta, and -gamma are members of a recently discovered family of proteins that contain disintegrin and metalloprotease domains and are related to fertilin, a protein involved in egg-sperm fusion. Based on this and evidence implicating meltrin-alpha in myoblast formation, we have investigated the possibility that meltrins may also play a role in the formation of MGC and osteoclasts. Using in situ RT-PCR, we have determined that murine mononuclear alveolar macrophages cultured under basal conditions express the transcript for meltrin-beta, but not for meltrin-alpha. However, meltrin-alpha mRNA appeared in mononuclear cells before cell fusion after treatment with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], a potent inducer of giant cell and osteoclast formation. Moreover, addition of meltrin-alpha antisense oligonucleotides to the cultures caused a 50% inhibition of giant cell formation. Similarly, meltrin-alpha antisense oligonucleotides inhibited by 70% the formation of multinucleated osteoclast-like cells expressing tartrate-resistant acid phosphatase (TRAP) in co-cultures of bone marrow cells and osteoblastic cells (2107) in the presence of 1,25(OH)2D3. Mononucleated TRAP-positive cells, induced by 1,25(OH)2D3 in the co-cultures, also expressed meltrin-alpha mRNA, but their number was not changed in the presence of meltrin-alpha antisense oligonucleotide. In contrast to mononuclear macrophages and osteoclast-like cells, murine bone marrow stroma and calvaria derived-cell lines (+/+ LDA.11 and 2107), primary cultures of calvaria cells, and primary cultures of bone marrow cells expressed both meltrin-alpha and -beta mRNA under basal conditions; whereas embryonic fibroblasts (NIH3T3) expressed only the meltrin-beta transcript. Upregulation of meltrin-alpha protein expression during cell fusion in alveolar macrophages and expression in osteoblastic cell lines were confirmed by Western blot analysis. These observations demonstrate that meltrins play a role in MGC and osteoclast formation from mononuclear precursors, as in the case with myotubes.

Expression and role of mannose receptor/terminal high-mannose type oligosaccharide on osteoclast precursors during osteoclast formation

“…In a recent study, Abe et al (1999) demonstrated that antisense oligonucleotides of meltrin involved in eggsperm fusion inhibited by 70% the formation of multinucleated osteoclast-like cells expressing TRAP in co-cultures of bone marrow cells. Moreover, anti-fusion regulatory protein-1/CD98 antibody has been shown to induce stimulated multinucleated giant cell and osteoclast formation (Higuchi et al 1998).…”

Osteoclast stimulatory transmembrane protein and dendritic cell–specific transmembrane protein cooperatively modulate cell–cell fusion to form osteoclasts and foreign body giant cells

“…(13) Therefore, although the functions of osteoclasts and FBGCs differ, they express common molecules, such as DC-STAMP, that function in cell-cell fusion. (3) To date, various molecules have been identified that regulate fusion of osteoclasts or macrophages, including DC-STAMP, ATP6v0d2, CD47, CD44, CD9, CD81, MFR, E-cadherin, and meltrin-a (3,(14)(15)(16)(17)(18)(19)(20)(21) ATP6v0d2-deficient mice show significant reductions in fusion of either cell type. (21) DC-STAMP-deficient osteoclasts or FBGCs show a complete lack of cell-cell fusion, a function specific for macrophage lineage fusion, since fertilization and myotube formation is normal in DC-STAMP-deficient mice.…”

Clinically aggressive central giant cell granulomas in two patients with neurofibromatosis 1

“…Although the MGCs seen in CGCG share some similarities with the osteoclast 26,27 , there are enough phenotypic differences to suggest that these may not be true osteoclasts 28 . It is generally accepted that these MGCs develop as a result of cell-cell fusion of mononuclear cells 29 . Possible origins of these mononuclear cells include endothelial cells 30 , myofibroblasts 31 with Noonan syndrome.…”