The accumulation of iron or aluminum can cause metabolic bone disease, but the mechanisms by which these agents affect bone metabolism remain uncertain. Since transferrin (Tf) can bind several different metals in plasma, equilibrium radioligand binding studies were performed to identify and characterize the Tf receptor in UMR-106-01 osteoblast-like cells; the role of Tf as a modifier of metal-induced changes in cell proliferation was also examined. Osteoblast-like cells grown in serum-free medium have approximately 40,000 Tf receptors on the cell membrane. Tf receptor expression increases during iron depletion and decreases with iron supplementation; the number of Tf receptors was also inversely related to both cell density and the rate of cell proliferation in vitro. Physiological levels of unsaturated Tf (5 microM) enhanced DNA synthesis in osteoblast-like cells maintained in serum-free medium, as measured by the incorporation of tritiated thymidine into DNA. Although neither 10 microM iron (Fe) nor 10 microM gallium (Ga), a known antiproliferative agent, altered DNA synthesis in UMR-106-01 cells during 48-h incubations in serum-free medium, both agents reduced the rate of DNA synthesis when added to serum-free medium containing 5 microM apo-Tf. Decreases in the incorporation of [3H] thymidine into DNA were also noted in osteoblast-like cells incubated for 48 h with 3 microM partially saturated iron Tf or gallium Tf. The results indicate that osteoblast-like cells have a single class of membrane receptors for Tf and that the regulation of Tf receptor expression in UMR-106-01 cells is similar to that in other cell types. The uptake of iron and gallium via the Tf-receptor complex can affect osteoblast proliferation, and such a mechanism may contribute to the bone cell toxicity of various metals.