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

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-α, -β, and -γ 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-α 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-β, but not for meltrin-α. However, meltrin-α 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-α antisense oligonucleotides to the cultures caused a 50% inhibition of giant cell formation. Similarly, meltrin-α 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-α mRNA, but their number was not changed in the presence of meltrin-α 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-α and -β mRNA under basal conditions; whereas embryonic fibroblasts (NIH3T3) expressed only the meltrin-β transcript. Upregulation of meltrin-α 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.

Authors and Affiliations

1. Division of Endocrinology and Metabolism, the UAMS Center for Osteoporosis and Metabolic Bone Diseases, and the John L. McClellan VA Geriatric Research, Education, and Clinical Center, University of Arkansas for Medical Sciences, 4301 West Markham, Mail Slot 587, Little Rock, Arkansas 72205, USA, US

   E. Abe, H. Mocharla, T. Yamate, Y. Taguchi & S. C. Manolagas

Received: 2 June 1998 / Accepted: 1 November 1998

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