alpha(v)beta(3) integrin was investigated in multiple myeloma in relation to the in vitro osteoclast-like activity of malignant plasma cells. Myeloma cells from patients with skeleton involvement overexpressed alpha(v)beta(3) and produced erosion pits on bone substrates, whereas this effect was not observed by cells from patients with no evidence of bone disease. We therefore explored the alpha(v)beta(3) transcriptional pathway in the bone-resorbing cells. Silencing of beta(3) chain abrogated the ability to produce erosion pits and extracellular signal-regulated kinase 1/2 phosphorylation resulting in the defective function of cFos and nuclear factor activator T cell 1, the terminal effectors of osteoclast activation. A similar defect occurred in constitutively beta(3)-deficient cells from patients with no skeleton disease. Microarray gene analysis of beta(3)(+) myeloma cells showed that several osteoclast-related genes were up-regulated. Their functions include the activation of receptor pathways beta(3) and c-fms that regulate several osteoclast functions. These data emphasize the postulated role of myeloma cells in multiple myeloma bone disease and suggest that their osteoclast-like activity is regulated, at least in vitro, by the beta(3) subunit of the integrin.