How Fra/AP-1 transcription factors control the bone niche

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Bone is a dynamic tissue regulated by the balance between osteoblasts, the bone forming cells and osteoclasts, the bone resorbing cells. Current concepts are that i) bone degradation is also regulated by the immune system ii) bone formation and inflammation interact and iii) bone and bone marrow form niches for the development and the survival of hematopoietic stem cells (HSC) and immune cells, in particular B-cells. Thus, interactions between bone remodeling and the immune system are necessary for proper bone homeostasis and HSC/immune cell niches. On one hand, we have recently demonstrated that Fra/AP-1 proteins are important transcription factors controlling the fate of osteoblasts. Preliminary data show that Fra-2 expression in osteoblasts induces systemic inflammation with increased macrophage infiltration but reduced B cell numbers in spleen and bone marrow. However, the molecular mechanisms how Fra-2 expression by osteoblasts induces inflammation and dampens B-cell development are not yet defined. On the other hand, Fra-1 is able to regulate B-cell development and humoral immune responses in cellautonomous manner. Preliminary results show that Fra-1 deletion in B-cells leads to a decreased bone volume in mice. The molecular mechanism leading to this bone alteration remains to be analyzed. Based on these two observations, we want to elucidate the crosstalk between the bone niche and immune cells, especially B-cells, regulated by Fra-1 and Fra-2 transcription factors. 1) We will describe the consequence of Fra-1 and Fra-2 deletion in B-cells on bone homeostasis and 2) analyze the effect of Fra-1 and Fra-2 expression in osteoblasts on B-cell development, humoral immune responses and inflammation. Hence, depicting the molecular mechanism underlying the crosstalk between osteoblast and immune cells in the bone marrow will add new insights in the comprehension of the bone marrow niches and bone cell-immune cell interactions.