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 phago cytic system it is conceivable that bisphosphonates not only affect bo ne metabolism but also inflammatory responses. The migration of mononu clear cells into perivascular tissue is a central event in inflammator y reactions. We studied the effects of the aminobisphosphonate alendro nate on the transendothelial migration of human peripheral blood monon uclear cells in an in vitro model. Alendronate (at a concentration of 100 mu M) significantly increased the percentage of peripheral blood m ononuclear cells that migrated through endothelial cell monolayers. Si milar results were obtained with another aminobisphosphonate, viz, pam idronate. An overnight treatment of the endothelial cell monolayers wi th alendronate did not alter the rate of peripheral blood mononuclear cells that subsequently migrated. The overnight cultivation of the per ipheral blood mononuclear cells in the presence of alendronate resulte d in an increased surface expression of CD54 (intercellular adhesion m olecule-1, ICAM-1) in both CD 14(+) and CD3(+) cells; in CD14(+) cells also the expression of CD49d (alpha(4) subunit of late activation ant igen-4, VLA-4) increased after alendronate treatment. Alendronate trea tment of peripheral blood mononuclear cells also resulted in an increa sed production of interleukin-1 beta (IL-1 beta), tumor necrosis facto r-alpha (TNF-alpha), and interferon-gamma (IFN-gamma). We conclude tha t 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 p roinflammatory cytokines, influence the expression of certain adhesion molecules and thereby facilitate transendothelial migration. These ef fects could be related to the transient leukopenia reported following intravenous administration of relatively high doses of aminobisphospho nates for the treatment of hypercalcemia of malignancy.