REGULATION OF OSTEOCLASTOGENESIS BY ANTISENSE OLIGODEOXYNUCLEOTIDES SPECIFIC TO ZINC-FINGER NUCLEAR TRANSCRIPTION FACTORS EGR-1 AND WT1 IN RAT BONE-MARROW CULTURE SYSTEM

Differentiation of osteoclasts is defined by the transcription factors expressed in response to bone microenvironments. In this work, we exa mined the effects of an expressional blockage of Egr-1 and/or WT1 on t he differentiation of osteoclasts using specific antisense oligodeoxyn ucleotides (ODN). In a culture system forming preosteoclast-like cells (POC) from rat bone marrow cells depleted of marrow stromal cells, PO C formation was markedly stimulated by the addition of Egr-1 antisense ODN compared to that in cultures in which sense ODN was added, wherea s Egr-1 antisense ODN inhibited the formation of macrophage-like cells . The formation of multinucleated osteoclast-like cells was also stimu lated by the addition of Egr-1 antisense ODN in whole bone marrow cult ures. In contrast, WT1 antisense ODN did not affect POC formation indu ced by the treatment with Egr-1 antisense ODN; however, WT1 antisense ODN dramatically suppressed the formation of osteoclast-like multinucl eated cells induced by the blockage of Egr-1 expression using Egr-1 an tisense ODN. These data suggest that Egr-1 acts as the suppressor, not as the inducer, in osteoclastogenesis. The findings also suggested th at WT1 could be involved in the multinucleation step of osteoclastogen esis, at least when Egr-1 expression was blocked.