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Requirement for NF-kappaB in osteoclast and B-cell development
G Franzoso1, L Carlson, L Xing
1Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abstract:
NF-kappaB is a family of related, dimeric transcription factors that are readily activated in cells by signals associated with stress or pathogens. These factors are critical to host defense, as demonstrated previously with mice deficient in individual subunits of NF-kappaB. We have generated mice deficient in both the p50 and p52 subunits of NF-kappaB to reveal critical functions that may be shared by these two highly homologous proteins. We now demonstrate that unlike the respective single knockout mice, the p50/p52 double knockout mice fail to generate mature osteoclasts and B cells, apparently because of defects that track with these lineages in adoptive transfer experiments. Furthermore, these mice present markedly impaired thymic and splenic architectures and impaired macrophage functions. The blocks in osteoclast and B-cell maturation were unexpected. Lack of mature osteoclasts caused severe osteopetrosis, a family of diseases characterized by impaired osteoclastic bone resorption. These findings now establish critical roles for NF-kappaB in development and expand its repertoire of roles in the physiology of differentiated hematopoietic cells.
Insights
Mice lacking both p50 and p52 subunits of Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) show severe developmental defects. These NF-kappaB deficient mice fail to develop mature osteoclasts and B cells, leading to impaired immunity and bone structure.
Area of Science:
- Immunology
- Cell Biology
- Developmental Biology
Background:
- Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) transcription factors are crucial for host defense against stress and pathogens.
- Previous studies highlighted the importance of individual NF-kappaB subunits in cellular functions.
- The high homology between p50 and p52 subunits suggested potentially shared critical functions.
Purpose of the Study:
- To investigate the shared functions of p50 and p52 subunits of NF-kappaB.
- To determine the in vivo consequences of a combined deficiency in p50 and p52 NF-kappaB subunits.
Main Methods:
- Generation of mice deficient in both p50 and p52 NF-kappaB subunits (double knockout).
- Analysis of B cell and osteoclast development in double knockout mice.
- Adoptive transfer experiments to track lineage-specific defects.
- Assessment of thymic and splenic architecture.
- Evaluation of macrophage functions.
Main Results:
- p50/p52 double knockout mice exhibit a complete failure to generate mature osteoclasts and B cells.
- Defects in osteoclast and B-cell maturation were confirmed through lineage tracing in adoptive transfer experiments.
- These mice displayed significantly impaired thymic and splenic architectures.
- Macrophage functions were also markedly impaired in the double knockout model.
- Severe osteopetrosis was observed due to the lack of mature osteoclasts, indicating impaired bone resorption.
Conclusions:
- The combined deficiency of p50 and p52 NF-kappaB subunits reveals critical, non-redundant roles in the development of osteoclasts and B cells.
- These findings establish essential roles for NF-kappaB in hematopoietic cell development and differentiation.
- The study expands the known physiological functions of NF-kappaB in mature hematopoietic cells and immune responses.