Aggregation of mononucleated precursors triggers cell surface expression of αvβ3 integrin, essential to formation of osteoclast-like multinucleated cells

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Abstract
αvβ3 is a key integrin mediating adhesion of multinucleated osteoclasts during bone resorption. 1,25-dihydroxyvitamin D3 upregulates αvβ3 integrin expression in mononucleated osteoclast precursors and concomitantly stimulates their differentiation into osteoclasts. This suggests that this integrin could play a major role during osteoclast differentiation.We have developed an in vitro model, in which 1,25-dihydroxyvitamin D3 sequentially modifies the behavior of macrophages: Ìt first induces rounding up of these cells, then their subsequent aggregation and spreading, which finally leads to cell fusion and the formation of osteoclast-like multinucleated giant cells. We show that, while 1,25-dihydroxyvitamin D3 stimulates the de novo synthesis of αvβ3 in macrophages early in this process, its accumulation on the surface is triggered by cell aggregation. A high level of integrin αvβ3 cell surface expression correlates with macrophage spreading preceding fusion. This was confirmed by means of novel cell permeable peptides containing the C-terminal sequence of the integrin β3 tail to specifically block αvβ3 function. Although this peptide has no effect on the aggregation step, it disrupts the spreading of osteoclast precursors and consequently inhibits their fusion. These findings suggest a novel role of the integrin αvβ3 in a discrete step of osteoclast differentiation.