OSTEOPETROSIS IN MICE LACKING NF-KAPPA-B1 AND NF-KAPPA-B2

The nfkb1 and nfkb2 genes encode closely related products regulating i mmune and inflammatory responses. Their role during development and di fferentiation remains unclear. The generation of nfkb1 null mice (p50( -/-)) resulted in altered immune responses, but had no effect on devel opment(4). Similarly, nfkb2 knockout mice (p52(-/-)) did not show deve lopmental defects (J.C. et ol., manuscript submitted). We have investi gated the potential for in vivo compensatory functions of these genes by generating double-knockout mice. The surprising result was that the animals developed osteopetrosis because of a defect in osteoclast dif ferentiation, suggesting redundant functions of NF-kappa B1 and NF-kap pa B2 proteins in the development of this cell lineage. The osteopetro tic phenotype was rescued by bone marrow transplantation, indicating t hat the hematopoietic component was impaired. These results define a n ew mouse osteopetrotic mutant and implicate NF-kappa B proteins in bon e development, raising new directions in the treatment of bone disorde rs.