INTERLEUKIN-6 ANTISENSE DEOXYOLIGONUCLEOTIDES INHIBIT BONE-RESORPTIONBY GIANT-CELLS FROM HUMAN GIANT-CELL TUMORS OF BONE

The effects of antisense constructs to IL-6 on the bone-resorbing capa city of purified giant cells from giant cell tumors of bone were exami ned to further define the role of IL-6 in human osteoclastic bone reso rption. In addition, we wanted to determine the utility of antisense c onstructs to cytokines produced by osteoclasts as probes to identify t he molecular events responsible for the bone-resorptive process. Giant cells were cultured on sperm whale dentin for 24 h in the presence of fluoresceinated antisense or scrambled antisense deoxyoligonucleotide s complementary to IL-6 mRNA. The giant cells actively incorporated th ese oligonucleotides, as evidenced by their intense fluorescence. The number of resorptive lacunae formed and the area of the dentin resorbe d were significantly decreased in cultures of giant cells treated with antisense IL-6 constructs compared with control cultures treated with scrambled antisense constructs to IL-6 (60 +/- 13 versus 12 +/- 6 lac unae and 1.2 +/- 0.3 versus 0.26 +/- 0.1 x 10(5) mu m(2)). IL-6 levels in conditioned media from giant cell cultures treated with IL-6 antis ense constructs were fourfold lower than those in control media obtain ed from giant cells treated with scrambled antisense constructs to IL- 6. These data confirm the capacity of IL-6 antisense oligomers to bloc k IL-6 production by these cells. These observations show that IL-6 pl ays an important role in the bone-resorptive process of human osteocla sts and suggest that antisense constructs to cytokines produced by bon e cells may be useful for determining the molecular events occurring d uring bone resorption.