Osteopetrosis in mice lacking NF-kappa B1 and NF-kappa B2

The nfkb1 and nfkb2 genes encode closely related products regulating immune and inflammatory responses. Their role during development and differentiation remains unclear. The generation of nfkb1 null mice (p50(-/-)) resulted in altered immune responses, but had no effect on development(4). Similarly, nfkb2 knockout mice (p52(-/-)) did not show developmental defects (J.C. et ol., manuscript submitted). We have investigated 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 differentiation, suggesting redundant functions of NF-kappa B1 and NF-kappa B2 proteins in the development of this cell lineage. The osteopetrotic phenotype was rescued by bone marrow transplantation, indicating that the hematopoietic component was impaired. These results define a new mouse osteopetrotic mutant and implicate NF-kappa B proteins in bone development, raising new directions in the treatment of bone disorders.