C-FOS ANTISENSE DNA INHIBITS PROLIFERATION OF OSTEOCLAST PROGENITORS IN OSTEOCLAST DEVELOPMENT BUT NOT MACROPHAGE DIFFERENTIATION IN-VITRO

We previously reported that osteoclast formation in vitro, by cocultur e of mouse bone marrow and primary osteoblastic cells, occurs in two p hases: proliferation of osteoclast progenitors followed by terminal di fferentiation into mature osteoclasts, Using this coculture system, we examined the effects of c-fos antisense and sense phosphorothioate ol igonucleotides on osteoclast development and macrophage differentiatio n. Treatment with c-fos antisense for the first 4 days of coculture in hibited osteoclast formation in a dose-dependent fashion. However, whe n c-fos antisense was added during the second phase of coculture (4-6 days), osteoclast formation was unaffected, In contrast, c-fos antisen se treatment had no effect on the appearance of F4/80 antigen-positive cells of the macrophage lineage in these cultures or on the induction by colony stimulating factor-1 of macrophage colony formation in cult ures of mouse bone marrow cells in agar. Neither osteoclast differenti ation nor macrophage appearance was inhibited by adding control c-fos sense in the cocultures. When c-fos antisense was added into an assay of bone resorption by mature osteoclasts, pit formation on dentine sli ces was unaffected. These results indicate that c-fos plays an importa nt role in the proliferative phase of osteoclast progenitors in osteoc last development, but not in the terminal differentiation phase or in the bone resorbing activity of mature osteoclasts. c-fos antisense spe cifically inhibited osteoclast formation but had no effect on macropha ge development.