Head: Dr. rer. nat. Bettina Grötsch
Our group is currently investigating how changes in B cell development/activation affect bone homeostasis in diseases such as rheumatoid arthritis. In addition, we are investigating the importance of C type lectin receptors in bacterially induced bone loss. Our data will provide a better understanding of the complex interplay between the immune system and bone and provide a good approach to uncover new markers and treatment strategies in Rheumatoid Arthritis.
- B cells regulate bone remodeling in response to AP-1
Bone metabolism is a dynamic process with 10% bone renewal per year and is enabled by the function of bone-forming osteoblasts and bone-degrading osteoclasts. B cells have a close and diverse relationship with bone cells and directly influence bone remodeling. They differentiate from hematopoietic stem cells (HSCs) in supportive niches in bone. Pre-osteoblasts have previously been shown to be essential for the maturation of B cells. In contrast, the influence of bone marrow B cells on osteoblast differentiation and activity is poorly described.
The AP-1 transcription factor Fra2 has already been linked to both bone metabolism and B cell regulation. Loss of Fra2 at the very early pro-B cell stage greatly reduces the number of B cells in the bone marrow and spleen. However, it remains unclear whether Fra2 expression in B cells can also regulate bone turnover in inflammatory and non-inflammatory bone loss. Our main goal is to gain a better understanding of the molecular mechanisms underlying the role of B cells in osteoporosis in order to develop new treatment strategies.
- How does an immune response control osteoporosis?
Rheumatoid arthritis affects about 1% of the western world population, making it one of the most widespread autoimmune diseases. It causes changes in bone and articular cartilage, up to and including the destruction of these structures. The triggers that lead to progressive bone loss in the case of a corresponding genetic predisposition are still insufficiently researched. What is known is that bone loss is based on a shift in the balance of bone resorption (by osteoclasts) and bone formation (by osteoblasts). Recent studies have shown that immunoglobulin G (IgG) type antibodies produced by B cells during inflammation support osteoclast formation via the Fc-gamma receptor (Fcg).
Our preliminary studies show that Fcg and IFNg are simultaneously released on the surface of osteoclasts and exchange with each other. We therefore want to investigate when and how exactly these two signaling pathways interact to regulate osteoclast differentiation. In the longer term, the planned studies will help to develop new therapies against bone loss in autoimmune diseases such as rheumatoid arthritis.
- Membrane domain-dependent effects on the interaction of FcgRs and IFNgR during human osteoclastogenesis.
Osteoclasts are bone resorbing cells formed by cell-cell fusions of highly motile precursors. A specific membrane microenvironment enriched in lipids facilitates the process of cell fusion and osteoclast formation. This process is further regulated by Fc receptors, which are recruited to the lipid-rich membrane regions in response to IgG immune complexes. In contrast, however, osteoclast formation can also be blocked by inflammatory mediators. Little is known about involvement of membrane lipids in FcgR or IFNgR signaling in regulating osteoclast differentiation in health and disease. In this project, we aim to elucidate whether, and how, membrane phospholipid composition adjusts during the formation of bone resorbing cells, and whether FcgR/IFNgR signaling induces changes in the pattern of membrane lipid microdomains.
|Bettina Grötsch||Junior Research group leader|
|Elisabeth Schachtschabel||Medical doctoral student|
|Nicolai Lampert||Medical doctoral student|
|Shazia Ashraf||Scientific doctoral student|
Deutsche Forschungsgemeinschaft (DFG)
Single application: "B cells regulate bone remodeling in an AP-1 dependent manner" (since 2021)
- Moreyra PA, Berenbaum F, Danda D, Grötsch B, Stones SR, Viswanathan S. (2022) How the COVID-19 pandemic has affected rheumatology research. Nat Rev Rheumatol. 18(3):128-132.
- Grötsch B, Lux A, Rombouts Y, Hoffmann AC, Andreev D, Nimmerjahn F, Xiang W, Scherer HU, Schett G, Bozec A. (2019) Fra1 controls rheumatoid factor autoantibody production by bone marrow plasma cells and the development of autoimmune bone loss. J Bone Miner Res. 34(7):1352-1365.
- Grötsch B, Bozec A, Schett G. (2019) In Vivo Models of Rheumatoid Arthritis. Methods Mol Biol. 1914:269-280.
- Luo Y*, Grötsch B*, Hannemann N, Jimenez M, Ipseiz N, Uluckan O, Lin N, Schett G, Wagner EF, Bozec A. (2018) Fra-2 expression in osteoblasts regulates systemic inflammation and lung injury through osteopontin. Mol Cell Biol. 38(22):e00022-18. *equally contributed
- Meng X, Grötsch B, Luo Y, Knaup KX, Wiesener MS, Chen XX, Jantsch J, Fillatreau S, Schett G, Bozec A. (2018) Hypoxia-inducible factor-1α is a critical transcription factor for IL-10-producing B cells in autoimmune disease. Nat Commun. 9(1):251.
- Ubieta K, Garcia M, Grötsch B, Uebe S, Weber GF, Stein M, Ekici A, Schett G, Mielenz D, Bozec A. (2017) Fra-2 regulates B cell development by enhancing IRF4 and Foxo1 transcription. J Exp Med. 214(7):2059-2071.
- Derer A, Böhm C, Grötsch B, Grün JR, Grützkau A, Stock M, Böhm S, Sehnert B, Gaipl U, Schett G, Hueber AJ, David JP. (2016) Rsk2 controls synovial fibroblast hyperplasia and the course of arthritis. Ann Rheum Dis. 75(2):413-21.
- Mielenz D, Grötsch B, David JP. (2015) Repressing the repressor: Fra1 controls plasma cell generation. Oncotarget. 6(20):17861-2.
- Grötsch B, Brachs S, Lang C, Luther J, Derer A, Schlötzer-Schrehardt U, Bozec A, Fillatreau S, Berberich I, Hobeika E, Reth M, Wagner EF, Schett G, Mielenz D, David JP. (2014) The AP-1 transcription factor Fra1 inhibits follicular B cell differentiation into plasma cells. J Exp Med. 211(11):2199-212.
- Teufel S, Grötsch B, Luther J, Derer A, Schinke T, Amling M, Schett G, Mielenz D, David JP. (2014) Inhibition of bone remodeling in young mice by bisphosphonate displaces the plasma cell niche into the spleen. J Immunol. 193(1):223-33.