OsteoHematology

Hidden Secrets of the Osteohematopoietic Niche

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In the osteohematopoietic niche, home of bone and blood stem cells, the aging process affects both cell types. Clinically, this translates into fragility fractures and anemia. Myelodysplastic syndrome (MDS) is a human disease of age-related impaired function of the osteohematopoietic niche. To disentangle the alterations in MDS, a comprehensive approach with suitable disease models is required.

Using big data analysis of almost 900,000 patients, we recently found that MDS patients indeed have 2-fold higher risk for osteoporosis. Moreover, treatment of cytopenia in MDS may require continuous blood transfusions posing the risk of iron overload or treatment with erythropoiesis-stimulating agents, both of which negatively impact on bone. Despite recent progress, MDS is far from being fully understood and disease-specific therapies are missing. Elucidation of key mechanisms offers the prospects of improving bone function and hematopoietic function alike. This motivated researchers at the Bone Lab to take a closer look.

Principal Investigators

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Martina Rauner, PhD

Martina Rauner, PhD

«The area in which we made our first discovery that led to a patent – hopefully it will make it all the way into clinical application!»

Ulrike Baschant, PhD

Ulrike Baschant, PhD

«The area which taught me that the best scientific discoveries happen while you are busy formulating other hypotheses.»

Lorenz Hofbauer

Lorenz Hofbauer, MD

«What started as a research project on iron metabolism, turned out to be useful for treatment of major injury.»

Antonella Roetto, University of Torino, Italy
Ben Wielockx, Universitätsklinikum Dresden
Igor Theurl, Medical University Innsbruck, Austria
Yankel Gabet, Tel-Aviv University, Israel
Drorit Neumann, Tel-Aviv University, Israel
Jochen Schmitt, Center for Evidence-Based Healthcare, Universitätsklinikum Dresden
Uwe Platzbecker, Universitätsklinikum Leipzig
Martina Muckenthaler, Universitätsklinikum Heidelberg
Claudia Waskow, Fritz-Lipmann Institute, Jena
Anke Hannemann, Universität  Greifswald

Ledesma-Colunga MG, Baschant U, Weidner H, Alves TC, Mirtschink P, Hofbauer LC, Rauner M. Transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritis. Redox Biol. 2023;60:102616.

Weidner H, Wobus M, Hofbauer LC, Rauner M, Platzbecker U. Luspatercept mitigates bone loss driven by myelodysplastic neoplasms and estrogen-deficiency in mice. Leukemia. 2022:2715-2718.

Hartmann L, Hecker JS, Rothenberg-Thurley M, Rivière J, Jentzsch M, Ksienzyk B, Buck MC, van der Garde M, Fischer L, Winter S, Rauner M, Tsourdi E, Weidner H, Sockel K, Schneider M, Kubasch AS, Nolde M, Hausmann D, Lützner J, Goralski S, Bassermann F, Spiekermann K, Hofbauer LC, Schwind S, Platzbecker U, Götze KS, Metzeler KH. Compartment-specific mutational landscape of clonal hematopoiesis. Leukemia. 2022:2647-2655.

Awida Z, Hiram-Bab S, Bachar A, Saed H, Zyc D, Gorodov A, Ben-Califa N, Omari S, Omar J, Younis L, Iden JA, Graniewitz Visacovsky L, Gluzman I, Liron T, Raphael-Mizrahi B, Kolomansky A, Rauner M, Wielockx B, Gabet Y, Neumann D. Erythropoietin Receptor (EPOR) Signaling in the Osteoclast Lineage Contributes to EPO-Induced Bone Loss in Mice. Int J Mol Sci. 2022;23:12051.

Hettler F, Schreck C, Marquez SR, Engleitner T, Vilne B, Landspersky T, Weidner H, Hausinger R, Mishra R, Oellinger R, Rauner M, Naumann R, Peschel C, Bassermann F, Rad R, Istvanffy R, Oostendorp RAJ. Osteoprogenitor SFRP1 prevents exhaustion of hematopoietic stem cells via PP2A-PR72/130-mediated regulation of p300. Haematologica. 2022 Aug 11.

Baschant U, Altamura S, Steele-Perkins P, Muckenthaler MU, Spasić MV, Hofbauer LC, Steinbicker AU, Rauner M. Iron effects versus metabolic alterations in hereditary hemochromatosis driven bone loss. Trends Endocrinol Metab. 2022;33:652-663.

Herbig M, Jacobi A, Wobus M, Weidner H, Mies A, Kräter M, Otto O, Thiede C, Weickert MT, Götze KS, Rauner M, Hofbauer LC, Bornhäuser M, Guck J, Ader M, Platzbecker U, Balaian E. Machine learning assisted real-time deformability cytometry of CD34+ cells allows to identify patients with myelodysplastic syndromes. Sci Rep. 2022;12:870.

Hecker JS, Hartmann L, Rivière J, Buck MC, van der Garde M, Rothenberg-Thurley M, Fischer L, Winter S, Ksienzyk B, Ziemann F, Solovey M, Rauner M, Tsourdi E, Sockel K, Schneider M, Kubasch AS, Nolde M, Hausmann D, Paulus AC, Lützner J, Roth A, Bassermann F, Spiekermann K, Marr C, Hofbauer LC, Platzbecker U, Metzeler KH, Götze KS. CHIP and hips: clonal hematopoiesis is common in patients undergoing hip arthroplasty and is associated with autoimmune disease. Blood. 2021 4;138:1727-1732.

Wobus M, Mies A, Asokan N, Oelschlägel U, Möbus K, Winter S, Cross M, Weidner H, Rauner M, Hofbauer LC, Bornhäuser M, Platzbecker U. Luspatercept restores SDF-1-mediated hematopoietic support by MDS-derived mesenchymal stromal cells. Leukemia. 2021;35:2936-2947.

Rauner M, Murray M, Thiele S, Watts D, Neumann D, Gabet Y, Hofbauer LC, Wielockx B. Epo/EpoR signaling in osteoprogenitor cells is essential for bone homeostasis and Epo-induced bone loss. Bone Res. 2021 13;9:42.

Ledesma-Colunga MG, Weidner H, Vujic Spasic M, Hofbauer LC, Baschant U, Rauner M. Shaping the bone through iron and iron-related proteins. Semin Hematol. 2021;58:188-200.

Meng X, Wielockx B, Rauner M, Bozec A. Hypoxia-Inducible Factors Regulate Osteoclasts in Health and Disease. Front Cell Dev Biol. 2021 18;9:658893.

Hannemann A, Nauck M, Völzke H, Weidner H, Platzbecker U, Hofbauer LC, Rauner M, Baschant U. Interactions of Anemia, FGF-23, and Bone in Healthy Adults-Results From the Study of Health in Pomerania (SHIP). J Clin Endocrinol Metab. 2021 Jan 1;106:e288-e299.

Ledesma-Colunga MG,Baschant U, Fiedler IAK, Busse B, Hofbauer LC, Muckenthaler MU, Altamura S, Rauner M. Disruption of the hepcidin/ferroportin regulatory circuitry causes low axial bone mass in mice. 2020;137:115400.

Weidner H, Baschant U, Lademann F, Ledesma Colunga MG, Balaian E, Hofbauer C, Misof BM, Roschger P, Blouin S, Richards WG, Platzbecker U, Hofbauer LC, Rauner M. Increased FGF-23 levels are linked to ineffective erythropoiesis and impaired bone mineralization in myelodysplastic syndromes. JCI Insight. 2020;5:e137062.

Pagani A, Pettinato M, Colucci S, Dulja A, Rauner M, Nai A, Camaschella C, Altamura S, Muckenthaler MU, Silvestri L. Hemochromatosis proteins are dispensable for the acute hepcidin response to BMP2. Haematologica. 2020 Oct 1;105(10):e493.

Balaian E, Weidner H, Wobus M, Baschant U, Jacobi A, Mies A, Bornhäuser M, Guck J, Hofbauer LC, Rauner M, Platzbecker U. Effects of rigosertib on the osteo-hematopoietic niche in myelodysplastic syndromes. Ann Hematol. 2019; 98:2063-2072.

Jacome-Galarza CE, Percin GI, Muller JT, Mass E, Lazarov T, Eitler J, Rauner M, Yadav VK, Crozet L, Bohm M, Loyher PL, Karsenty G, Waskow C, Geissmann F. Developmental origin, functional maintenance and genetic rescue of osteoclasts. Nature. 2019;568:541-545.

Rauner M, Baschant U, Roetto A, Pellegrino RM, Rother S, Salbach-Hirsch J, Weidner H, Hintze V, Campbell G, Petzold A, Lemaitre R, Henry I, Bellido T, Theurl I, Altamura S, Colucci S, Muckenthaler MU, Schett G, Komla Ebri D, Bassett JHD, Williams GR, Platzbecker U, Hofbauer LC. Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signaling. Nat Metab. 2019;1:111-124.

Balaian E, Wobus M, Weidner H, Baschant U, Stiehler M, Ehninger G, Bornhäuser M, Hofbauer LC, Rauner M, Platzbecker U. Erythropoietin inhibits osteoblast function in myelodysplastic syndromes via the canonical Wnt pathway. Haematologica. 2018;103:61-68.

Weidner H, Rauner M, Trautmann F, Schmitt J, Balaian E, Mies A, Helas S, Baschant U, Khandanpour C, Bornhäuser M, Hofbauer LC, Platzbecker U. Myelodysplastic syndromes and bone loss in mice and men. Leukemia. 2017;31:1003-1007.

Rauner M, Franke K, Murray M, Singh RP, Hiram-Bab S, Platzbecker U, Gassmann M, Socolovsky M, Neumann D, Gabet Y, Chavakis T, Hofbauer LC, Wielockx B. Increased EPO levels are associated with bone loss in mice lacking PHD2 in EPO-producing cells. J Bone Miner Res. 2016;31:1877-1887.

Baschant U, Rauner M, Balaian E, Weidner H, Roetto A, Platzbecker U, Hofbauer LC. Wnt5a is a key target for the pro-osteogenic effects of iron chelation on osteoblast progenitors. Haematologica. 2016;101:1499-1507.

Bulycheva E, Rauner M, Medyouf H, Theurl I, Bornhäuser M, Hofbauer LC, Platzbecker U. Myelodysplasia is in the niche: novel concepts and emerging therapies. Leukemia. 2015;29:259-268.

Research Question

Bone and bone marrow house skeletal and blood stem cells. In myelodysplastic syndrome, a disease of the elderly, both functions are severely impaired, but the sequence of events and critical checkpoint for disease progression have remained unclear.

Approach

We study patients with MDS and preclinical MDS models. Our focus is on hypoxia pathways and the role of iron metabolism and overload on bone and bone marrow function. We explore novel MDS drugs, iron chelators, and bone marrow transplantation to unravel the osteohematopoietic niche function in health and disease.

Projects

  • Role of transferrin receptor-2 (Tfr2) in the osteohematopoietic niche
  • Mechanisms of Tfr1-mediated iron uptake in bone and effects of iron on bone cell bioenergetics
  • Defining the role of the iron-sensor Tfr2 in ossification processes
  • Role of Tfr2 in inflammatory bone diseases
  • Mechanisms of bone loss associated with MDS
  • Hypoxia signaling in bone
  • Effects of glucocorticoid excess on the osteohematopoietic niche

Funding

Funded by grants from DFG, especially within the DFG-Research Unit FerrOs (FOR5146). Two patent applications have been generated from our research on Tfr2.

Explained