EFFECTS OF LEAD ON OSTEOCLAST-LIKE CELL-FORMATION IN MOUSE BONE-MARROW CELL-CULTURES

To examine an effect of lead (Pb) on the process of osteoclast-like cell formation from its progenitors, we used a mouse bone marrow culture system in which osteoclast-like multinucleated cells (MNCs) were formed in response to bone-resorbing agents. In a 9-day culture period, Pb dose-dependently stimulated MNC formation over the concentration range 2-10 mu M, whereas at 40 mu M Pb, MNC formation declined. In an 11-day culture period, MNC formation reached a maximum at 5 mu M Pb and decreased with increasing concentration of Pb at 10-40 mu M. Pb-stimulated MNC formation was inhibited by both indomethacin and SC19220, an antagonist of prostaglandin E(2) (PGE(2)) receptor. Pb stimulated the production of PGE(2) in marrow cell cultures, suggesting that Pb-stimulated MNC formation is dependent on the production of PGE(2). 3-Isobutyl-1-methylxanthine potentiated Pb-stimulated MNC formation and 2',5'-dideoxyadenosine, an inhibitor of adenylate cyclase, inhibited it. A calcium ionophore A23187 increased Pb-induced MNC formation and verapamil, a calcium channel blocker, depressed it. It is possible that a PGE(2)-induced increase in the levels of cyclic adenosine 3',5'-monophosphate (cAMP) and calcium ions in marrow cells is involved in Pb-induced MNC formation. Pb and parathyroid hormone showed a synergistic stimulation on MNC formation. From these results, Pb is thought to induce osteoclast-like cell formation by a mechanism involving PGE(2) which increases the intracellular levels of cAMP and calcium ions.