REQUIREMENT FOR NF-KAPPA-B IN OSTEOCLAST AND B-CELL DEVELOPMENT

NF-kappa B is a family of related, dimeric transcription factors that are readily activated in cells by signals associated with stress or pa thogens. These factors are critical to host defense, as demonstrated p reviously with mice deficient in individual subunits of NF-kappa B. We have generated mice deficient in both the p50 and p52 subunits of NF- kappa B to reveal critical functions that may be shared by these two h ighly homologous proteins. We now demonstrate that unlike the respecti ve single knockout mice, the p50/p52 double knockout mice fail to gene rate mature osteoclasts and B cells, apparently because of defects tha t track with these lineages in adoptive transfer experiments. Furtherm ore, these mice present markedly impaired thymic and splenic architect ures and impaired macrophage functions. The blocks in osteoclast and B -cell maturation were unexpected. Lack of mature osteoclasts caused se vere osteopetrosis, a family of diseases characterized by impaired ost eoclastic bone resorption. These findings no iv establish critical rol es for NF-kappa B in development and expand its repertoire of roles in the physiology of differentiated hematopoietic cells.