INHIBITORY AND STIMULATORY EFFECTS OF PROSTAGLANDINS ON OSTEOCLAST DIFFERENTIATION

The effect of prostaglandins (PGs) on osteoclast differentiation, an i mportant point of control for bone resorption, is poorly understood. A fter an initial differentiation phase that lasts at least 4 days, muri ne monocytes, cocultured with UMR106 osteoblastic cells (in the presen ce of 1,25-dihydroxyvitamin D-3) give rise to tartrate-resistant acid phosphatase (TRAP) positive osteoclast-like cells that are capable of lacunar bone resorption. PGE(2) strongly inhibits TRAP expression and bone resorption in these cocultures. To examine further the cellular m echanisms associated with this inhibitory effect, we added PGE(2) to m onocyte/UMR106 cocultures at specific times before, during, and after this initial 4-day differentiation period. To determine whether this P GE(2) inhibition was dependent on the type of stromal cell supporting osteoclast differentiation, we also added PGE(2) to cocultures of mono cytes with ST2 preadipocytic cells. Inhibition of bone resorption was greatly reduced when the addition of PGE(2) to monocyte/UMRI06 cocultu res was delayed until the fourth day of incubation; when delayed until the seventh day, inhibition did not occur. PGE(2) inhibition of bone resorption was concentration-dependent and at 10(-6) M was also mediat ed by PGE(1) and PGF(2 alpha). In contrast to its effects on monocyte/ UMR106 cocultures, PGE(2) stimulated bone resorption in monocyte/ST2 c ocultures. Both ST2 cells and UMR106 cells were shown to express funct ional receptors for PGE(2). These results show that PGs strongly influ ence the differentiation of osteoclast precursors and that this effect is dependent not only on the type and dose of PG administered, but al so on the nature of the bone-derived stromal cell supporting this proc ess.