B cells regulate bone remodeling in an AP-1 dependent manner

• Applicant: Dr. Bettina Grötsch
• Subject Area: Rheumatology ; Immunology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 457583243

In the last two decades, numerous scientists have highlighted the interactions between bone and immune cells as well as their overlapping regulatory mechanisms. For example, osteoblasts, the bone-forming cells, regulate hematopoietic stem cell niches from which all blood and immune cells are derived. It has been previously demonstrated that especially pre-osteoblasts are essential for B cell commitment. In contrary, the impact of bone marrow B cells on osteoblast differentiation and activity is still not fully described. Interestingly, the AP-1 (Activator Protein-1) transcription factor Fra2 is an important regulator of skeletogenesis and early B cell development. It remains however, unclear whether Fra2 expression in B cells can also regulate bone turnover in inflammatory and non-inflammatory bone loss. By analyzing B cell specific conditional Fra2 knockout mice (Fra2Bcell) we will firstly address the B cell specific role of Fra2 on bone homeostasis. Preliminary results point to an osteopetrotic phenotype due to increased osteoblast numbers. Osteoblast differentiation and activity is controlled by canonical Wnt signaling pathway that is tightly regulated by antagonists of the sclerostin (SOST) and Dickkopf (Dkk) families. Interestingly ChIP sequencing of wild-type bone marrow B cells identified Dkk1 to be a potential Fra2 target gene. In addition, Dkk1 gene expression was markedly decreased in CD19+ bone marrow cells of Fra2Bcell mice. So far, it was not described that B cells could directly affect osteoblast growth. Therefore, we will define the molecular exchange between Fra2 B cells and osteoprogenitor cells. Secondly, to rule out the impact of Dkk1 expression in B cells on bone homeostasis, we will use mouse models with B cell specific deletion of Dkk1 (Dkk1CD19 and Dkk1mb1) to analyze B cell development and bone homeostasis in respect of Wnt/ß-catenin signaling. Thirdly, the observed steady state osteopetrotic phenotype of Fra2Bcell mice suggests that these mice might be protected against ovariectomy or inflammatory induced osteoporosis. Hereby, we want to address whether Fra2 or Dkk1 deficiency in B cells could rescue post-menopausal or inflammatory induced osteoporosis through the modulation of bone formation.In short, our work will depict the role of Fra2 in B cells as central actors in Wnt/ß-catenin signaling to orchestrate bone homeostasis and its implications during osteoporosis development. Our overall goal is to understand the molecular mechanisms underlying the role of B cells in osteoporosis. Research in this field has great potential to provide a better understanding of the pathogenesis of several diseases affecting both the bone and immune systems, thus providing the molecular basis for novel therapeutic strategies.

• DFG Programme: Research Grants