Organ cross-talk controlled by transcription factors, nutrients and cytokines: bone homeostasis and cancer
Final Report Abstract
Our work has demonstrated the important role of the AP-1 transcription factor, specifically, the Fra-2 and Fra-1 proteins, in bone biology and bone metabolism. Using in vitro and in vivo gain- and loss-of-function approaches, we are analysing the role of these proteins in the differentiation of stromal bone cell types and their cross-talk with immune cells in the regulation of inflammation. We are also defining the importance of hypoxia within stromal and immune cell interaction during bone homeostasis or inflammatory bone disease development. Finally, we are defining the role of obesity and inflammation on the bone niche and the cancer cell niches in the bone. Overall, this study provided an important basis knowledge and a better understanding of how AP-1 transcription factor, hypoxia as well as obesity affect osteoporosis, inflammatory bone disease and bone metastases in the perspective of developing new therapeutic strategies. However, further studies would be necessary to continue in order to pursue the development of therapeutic options against inflammatory bone loss.
Publications
- FOSL2 promotes leptin gene expression in human and mouse adipocytes. The Journal of clinical investigation 2012. vol 122: 1010-1021
Wrann CD, Bozec A, Eguchi J, Xu Z, Mikkelsen T, Gimble J, Nave H, Wagner EF, Ong SE, Rosen ED
(See online at https://doi.org/10.1172/JCI58431) - Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. The Journal of clinical investigation 2012. vol 122: 1791-1802
Harre U, Georgess D, Bang H, Bozec A, Axmann R, Ossipova E, Jakobsson PJ, Baum W, Nimmerjahn F, Szarka E Sarmay, G, Krumbholz, G, Neumann, E, Toes, R, Scherer, H. U, Catrina, A. I, Klareskog, L, Jurdic, P, Schett, G
(See online at https://doi.org/10.1172/JCI60975) - Osteoblast-specific expression of Fra-2/AP-1 controls Adiponectin/Osteocalcin expression and affects metabolism. Journal of cell science 2013 Dec 1;126(Pt 23):5432-40
Bozec A, Bakiri L, Jimenez M, Rosen ED, Catala-lehren P., Schinke T, Schett G., Amling M and Wagner EF
(See online at https://doi.org/10.1242/jcs.134510) - Sclerostin inhibition reverses systemic, periarticular and local bone loss in arthritis. Ann Rheum Dis. 2013 Oct 1;72(10):1732-6
Chen XX., Baum W., Dwyer D., Stock M., Schwabe K., Ke HZ., Stolina M., Schett G, Bozec A.
(See online at https://doi.org/10.1136/annrheumdis-2013-203345) - Fra-2/AP-1 controls adipocyte differentiation and survival by regulating PPARγ and hypoxia. Cell Death Differ. 2014 Apr;21(4):655-64
Luther J, Ubieta K, Hannemann N, Jimenez M, Garcia M, Zech C, Schett G, Wagner EF, Bozec A
(See online at https://doi.org/10.1038/cdd.2013.198) - T. cell co-stimulation molecule CD80/86 inhibits osteoclasts differentiation by inducing the IDO/tryptophan pathway. Science translational medicine 2014 May 7;6(235):235
Bozec A, Zaiss M, Kagwiria R, Voll R, Rauh M, Chen Z, Mueller-Schmucker S, Kroczek R A, Heinzerling L, Moser M, Mellor A L, David JP, Schett G
(See online at https://doi.org/10.1126/scitranslmed.3007764) - Adipose-derived stromal cells expressing Fra-1 inhibit osteoarthritis. Arthritis & Rheumatology. 2015 Jan;68(1):138-51
Schwabe K, Garcia M, Ubieta K, Hannemann N, Herbort B, Luther J, Noël D, Jorgensen C, Casteilla L, David J P, Stock M, Herrmann M, Schett G, Bozec A
(See online at https://doi.org/10.1002/art.39425) - Microbiota from obese mice regulate hematopoietic stem cell differentiation by altering the bone niche. Cell Metabolism. 2015 Nov 3;22(5):886-94
Luo Y, Chen G L, Hannemann N, Ipseiz N, Krönke G, Bäuerle T, Munos L, Wirtz S, Schett G, Bozec A
(See online at https://doi.org/10.1016/j.cmet.2015.08.020) - High fat diet increases melanoma cell growth in the bone marrow by inducing osteopontin and interleukin 6. Oncotarget. 2016 May 3;7(18):26653-69
Chen G, Luo Y., Eriksson D, Meng X, Qian C, Bäuerle T., Chen X, Schett G, Bozec A
(See online at https://doi.org/10.18632/oncotarget.8474) - Th2 and eosinophil responses suppress inflammatory arthritis. Nat Comm. 2016 Jun 7;7:11596
Chen Z, Oeser K, Hueber A, Kleyer A, Voehringer D, Schett G, Bozec A
(See online at https://doi.org/10.1038/ncomms11596) - Fra-2 regulates B cell development by enhancing IRF4 and Foxo1 transcription. JEM. 2017. 20160514–13
Ubieta K, Garcia M, Grötsch B, Uebe S, Weber G, Stein M, Ekici A, Schett G, Mielenz D, Bozec A
(See online at https://doi.org/10.1084/jem.20160514) - The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages. J Immunol. 2017 Mar 15
Hannemann N, Jordan J, Paul S, Reid S, Baenkler HW, Sonnewald S, Bäuerle T, Vera J, Schett G, Bozec A
(See online at https://doi.org/10.4049/jimmunol.1601330)
