Abstract
Mice deficient in the matrix metalloproteinase MT1-MMP display defects in tissue development and angiogenesis, together with a complex bone phenotype characterized by several skeletal abnormalities and osteopenia. OCs and giant cells are multinucleated cells arising from the fusion of myeloid progenitors/macrophages that specialize respectively in bone resorption and engulfment of pathogens and foreign bodies. Our work identifies MT1-MMP as a novel component of the macrophage fusion machinery during OC and giant cell formation in vitro and in vivo. MT1-MMP is required for the proper lamellipodia formation and motility required to achieve proximity between fusioncompetent myeloid cells; and roles of MT1-MMP in subsequent steps of the fusion process cannot be ruled out. For example, MT1-MMP might exert additional functions at fusion sites by forming molecular complexes with CD44 or tetraspanin proteins. Interestingly, the contribution of MT1-MMP to macrophage motility and fusion does not involve its catalytic activity. Instead, the MT1-MMP-cytosolic tail, in particular Tyr(573), is required to bind the adaptor protein p130Cas and regulate localized Rac1 activity in myeloid progenitors. Modulation of this novel MT1-MMPp130Cas- Rac1 signaling pathway in macrophages might have potential in the treatment of disorders involving increased OC activity or uncontrolled giant cell formation.