The effect of alendronate on cytokine production, adhesion molecule expression, and transendothelial migration of human peripheral blood mononuclear cells

Since both osteoclasts and macrophages belong to the mononuclear phagocytic system it is conceivable that bisphosphonates not only affect bone metabolism but also inflammatory responses. The migration of mononuclear cells into perivascular tissue is a central event in inflammatory reactions. We studied the effects of the aminobisphosphonate alendronate on the transendothelial migration of human peripheral blood mononuclear cells in an in vitro model. Alendronate (at a concentration of 100 mu M) significantly increased the percentage of peripheral blood mononuclear cells that migrated through endothelial cell monolayers. Similar results were obtained with another aminobisphosphonate, viz, pamidronate. An overnight treatment of the endothelial cell monolayers with alendronate did not alter the rate of peripheral blood mononuclear cells that subsequently migrated. The overnight cultivation of the peripheral blood mononuclear cells in the presence of alendronate resulted in an increased surface expression of CD54 (intercellular adhesion molecule-1, ICAM-1) in both CD 14(+) and CD3(+) cells; in CD14(+) cells also the expression of CD49d (alpha(4) subunit of late activation antigen-4, VLA-4) increased after alendronate treatment. Alendronate treatment of peripheral blood mononuclear cells also resulted in an increased production of interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma). We conclude that alendronate has a distinct effect on the transendothelial migration of human peripheral blood mononuclear cells in vitro. Alendronate may either directly or indirectly, e.g., by augmenting the production of proinflammatory cytokines, influence the expression of certain adhesion molecules and thereby facilitate transendothelial migration. These effects could be related to the transient leukopenia reported following intravenous administration of relatively high doses of aminobisphosphonates for the treatment of hypercalcemia of malignancy.