MACROPHAGE-COLONY-STIMULATING FACTOR DOWN-REGULATES MCSF-RECEPTOR EXPRESSION AND ENTRY OF PROGENITORS INTO THE OSTEOCLAST LINEAGE

Macrophage colony-stimulating factor (MCSF), although necessary for en try of precursors into the early preosteoclast pathway, inhibits osteo clastogenesis at high doses, To clarify the relationship between MCSF and osteoclast formation, we investigated the effect of exogenous MCSF in murine bone marrow culture, Precursor proliferation and the expres sion of MCSF-receptor were examined after 4 days of culture in the pre sence or absence of accessory stromal cells, In both mixed marrow and destromalized cell cultures, exogenous MCSF dose-dependently decreased I-125-MCSF binding (by 65 +/- 5.0% at 3500 and 87 +/- 16.7% at 7000 U /ml, respectively) while enhancing mononuclear cell proliferation afte r 3 days of exposure (by 2.8- and 6.3-fold, respectively). These effec ts were maintained 24 h after removal of exogenous MCSF and, as such, likely represented an MCSF-induced change in MCSF receptor-bearing cel ls. Exposure to exogenous MCSF (3500 U/ml) days 24 dose-dependently in hibited tartrate resistant acid phosphatase positive multinuclear cell (TRAP(+) MNC) formation counted at the end of day 7, by 643 +/- 4.1%. This inhibition of TRAP(+) MNC formation was preceded by a 92 +/- 9% decrease in the expression of carbonic anhydrase II mRNA measurable at 3 days, These results indicate that MCSF promotes proliferation of a population of cells expressing lower cognate receptor sites, Changes i n MCSF-receptor expression appear to modulate the final lineage select ion of the pluripotent monoblastic progenitor.