Osteopetrosis in mice lacking NF-κB1 and NF-κB2

Abstract

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. Similarly, nfkb2 knockout mice (p52-/-) did not show developmental defects (J.C. et al., 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-kappaB1 and NF-kappaB2 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-kappaB proteins in bone development, raising new directions in the treatment of bone disorders.

Genetic approaches in mice to understand Rel/NF-κB and IκB function: transgenics and knockouts

“…Bone remodeling is dependent on bone resorption by myeloid lineage-derived osteoclasts. Although osteoclast numbers are markedly reduced in these double mutant mice and nfkb1 7/7 nfkb2 7/7 osteoclast progenitors cannot di erentiate in vitro , transplantation of normal marrow into newborn nfkb1 7/7 nfkb2 7/7 mice only partially rescues this osteopetrotic phenotype (Franzoso et al, 1997;Iotsova et al, 1997). This indicates that the combined de®ciency of nfkb1 and nfkb2 a icts cells of a hemopoietic origin and the bone marrow microenvironment.…”

“…Indeed, mice lacking multiple Rel/NF-kB proteins often exhibit novel phenotypes or more severe versions of those phenotypes seen in single mutants. nfbk1 7/7 nfkb2 7/7 mice Mice de®cient in both nfkb1 and nfkb2, while phenotypically indistinguishable from control litter mates at birth, soon exhibit growth retardation and cranofacial abnormalities, the latter being a result of bone thickening due to osteopetrosis (Franzoso et al, 1997;Iotsova et al, 1997). Bone remodeling is dependent on bone resorption by myeloid lineage-derived osteoclasts.…”

Expression, signaling, and function of P2X7 receptors in bone

“…NF-κB is a transcription factor essential for osteoclast development [71,72]. In resting cells, inactive NF-κB resides in the cytoplasm and upon activation translocates to the nucleus where it regulates transcription of a variety of genes involved in cell proliferation, apoptosis, and inflammation [73,74].…”

Severe osteopetrosis, defective interleukin‐1 signalling and lymph node organogenesis in TRAF6‐deficient mice

“…To address whether failure of osteoclast formation is due to defects in accessory cells (osteoblast/stromal cells) or cells of the osteoclast lineage (Yoshida et al 1990;Soriano et al 1991;Grigoriadis et al 1994;Franzoso et al 1997;Iotsova et al 1997), we have performed in vitro culture experiments. Primary osteoblasts, derived from calvariae of newborn normal ddY mice were cocultured with splenocytes either from TRAF6 ¹/¹ mice or their normal littermates.…”