10 results on '"Wielockx, Ben"'
Search Results
2. Erythropoietin Receptor (EPOR) Signaling in the Osteoclast Lineage Contributes to EPO-Induced Bone Loss in Mice.
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Awida, Zamzam, Hiram-Bab, Sahar, Bachar, Almog, Saed, Hussam, Zyc, Dan, Gorodov, Anton, Ben-Califa, Nathalie, Omari, Sewar, Omar, Jana, Younis, Liana, Iden, Jennifer Ana, Graniewitz Visacovsky, Liad, Gluzman, Ida, Liron, Tamar, Raphael-Mizrahi, Bitya, Kolomansky, Albert, Rauner, Martina, Wielockx, Ben, Gabet, Yankel, and Neumann, Drorit
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ERYTHROPOIETIN receptors ,ERYTHROPOIETIN ,OSTEOCLASTOGENESIS ,BONE growth ,B cells ,BONE marrow ,MONOCYTES ,MICE - Abstract
Erythropoietin (EPO) is a pleiotropic cytokine that classically drives erythropoiesis but can also induce bone loss by decreasing bone formation and increasing resorption. Deletion of the EPO receptor (EPOR) on osteoblasts or B cells partially mitigates the skeletal effects of EPO, thereby implicating a contribution by EPOR on other cell lineages. This study was designed to define the role of monocyte EPOR in EPO-mediated bone loss, by using two mouse lines with conditional deletion of EPOR in the monocytic lineage. Low-dose EPO attenuated the reduction in bone volume (BV/TV) in Cx3cr1
Cre EPORf/f female mice (27.05%) compared to controls (39.26%), but the difference was not statistically significant. To validate these findings, we increased the EPO dose in LysMCre model mice, a model more commonly used to target preosteoclasts. There was a significant reduction in both the increase in the proportion of bone marrow preosteoclasts (CD115+ ) observed following high-dose EPO administration and the resulting bone loss in LysMCre EPORf/f female mice (44.46% reduction in BV/TV) as compared to controls (77.28%), without interference with the erythropoietic activity. Our data suggest that EPOR in the monocytic lineage is at least partially responsible for driving the effect of EPO on bone mass. [ABSTRACT FROM AUTHOR]- Published
- 2022
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3. Short-Term Hypoxia Dampens Inflammation in vivo via Enhanced Adenosine Release and Adenosine 2B Receptor Stimulation
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Kiers, Dorien, Wielockx, Ben, Peters, Esther, van Eijk, Lucas T, Gerretsen, Jelle, John, Aaron, Janssen, Emmy, Groeneveld, Rianne, Peters, Mara, Damen, Lars, Meneses, Ana M, Krüger, Anja, Langereis, Jeroen D, Zomer, Aldert L, Blackburn, Michael R, Joosten, Leo A, Netea, Mihai G, Riksen, Niels P, van der Hoeven, Johannes G, Scheffer, Gert-Jan, Eltzschig, Holger K, Pickkers, Peter, Kox, Matthijs, LS Klinisch Onderzoek Wagenaar, dI&I I&I-4, LS Klinisch Onderzoek Wagenaar, and dI&I I&I-4
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0301 basic medicine ,Adenosine ,medicine.medical_treatment ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,lcsh:Medicine ,Inflammation ,Pharmacology ,Systemic inflammation ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Mice ,0302 clinical medicine ,All institutes and research themes of the Radboud University Medical Center ,Endotoxin ,medicine ,Animals ,Humans ,Hypoxia ,Adenosine 2B receptor ,lcsh:R5-920 ,business.industry ,lcsh:R ,Receptors, Purinergic P1 ,Interleukin ,Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16] ,General Medicine ,Hypoxia (medical) ,Purinergic signalling ,Hypoxia-Inducible Factor 1, alpha Subunit ,Endotoxemia ,3. Good health ,Interleukin-10 ,Up-Regulation ,Interleukin 10 ,Disease Models, Animal ,030104 developmental biology ,Cytokine ,Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10] ,Cytokines ,medicine.symptom ,business ,lcsh:Medicine (General) ,030217 neurology & neurosurgery ,medicine.drug ,Research Paper - Abstract
Hypoxia and inflammation are closely intertwined phenomena. Critically ill patients often suffer from systemic inflammatory conditions and concurrently experience short-lived hypoxia. We evaluated the effects of short-term hypoxia on systemic inflammation, and show that it potently attenuates pro-inflammatory cytokine responses during murine endotoxemia. These effects are independent of hypoxia-inducible factors (HIFs), but involve augmented adenosine levels, in turn resulting in an adenosine 2B receptor-mediated post-transcriptional increase of interleukin (IL)-10 production. We translated our findings to humans using the experimental endotoxemia model, where short-term hypoxia resulted in enhanced plasma concentrations of adenosine, augmentation of endotoxin-induced circulating IL-10 levels, and concurrent attenuation of the pro-inflammatory cytokine response. Again, HIFs were shown not to be involved. Taken together, we demonstrate that short-term hypoxia dampens the systemic pro-inflammatory cytokine response through enhanced purinergic signaling in mice and men. These effects may contribute to outcome and provide leads for immunomodulatory treatment strategies for critically ill patients., Highlights • Short-term hypoxia attenuates the systemic pro-inflammatory cytokine response in vivo in both mice and men • The underlying mechanism involves adenosine 2B receptor-mediated enhanced production of anti-inflammatory interleukin-10 • These effects may contribute to outcome and provide leads for novel treatment strategies for critically ill patients Inflammation and short bouts of low oxygen levels are frequently encountered phenomena in severely ill patients admitted to the Intensive Care unit. This study investigated the effect of short-term low oxygen levels on the inflammatory response in both mice and humans. The results show that a short period of low levels of oxygen potently dampens inflammation, and identify the underlying mechanisms. These effects of low oxygen levels may contribute to the outcome of severely ill patients. Furthermore, the increased understanding of the underlying mechanisms provided by this study can be used to develop therapies to dampen inflammation in patients.
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- 2018
4. Haematopoietic prolyl hydroxylase-1 deficiency promotes M2 macrophage polarization and is both necessary and sufficient to protect against experimental colitis
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Van Welden, Sophie, De Vos, Martine, Wielockx, Ben, Tavernier, Simon J., Dullaers, Melissa, Neyt, Sara, Descamps, Benedicte, Devisscher, Lindsey, Devriese, Sarah, Van den Bossche, Lien, Holvoet, Tom, Baeyens, Ann, Correale, Carmen, D'Alessio, Silvia, Vanhove, Christian, De Vos, Filip, Verhasselt, Bruno, Breier, Georg, Lambrecht, Bart N., Janssens, Sophie, Carmeliet, Peter, Danese, Silvio, Elewaut, Dirk, Laukens, Debby, Hindryckx, Pieter, Van Welden, S, De Vos, M, Wielockx, B, Tavernier, Sj, Dullaers, M, Neyt, S, Descamps, B, Devisscher, L, Devriese, S, Van den Bossche, L, Holvoet, T, Baeyens, A, Correale, C, D'Alessio, S, Vanhove, C, De Vos, F, Verhasselt, B, Breier, G, Lambrecht, Bn, Janssens, S, Carmeliet, P, Danese, S, Elewaut, D, Laukens, D, and Hindryckx, P
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Lipopolysaccharides ,Male ,Colon ,Macrophages ,Interleukin-1beta ,NF-kappa B ,Procollagen-Proline Dioxygenase ,Endothelial Cells ,Dendritic Cells ,macrophages ,Hypoxia-Inducible Factor-Proline Dioxygenases ,Mice, Inbred C57BL ,Mice ,Bone Marrow ,prolyl hydroxylase-1 ,Animals ,Humans ,Colitis, Ulcerative ,Female ,dendritic cells ,haematopoietic cells ,Gene Deletion ,ulcerative colitis - Abstract
Prolyl hydroxylase domain-containing proteins (PHDs) regulate the adaptation of cells to hypoxia. Pan-hydroxylase inhibition is protective in experimental colitis, in which PHD1 plays a prominent role. However, it is currently unknown how PHD1 targeting regulates this protection and which cell type(s) are involved. Here, we demonstrated that Phd1 deletion in endothelial and haematopoietic cells (Phd1(f/f)Tie2:cre) protected mice from dextran sulphate sodium (DSS)-induced colitis, with reduced epithelial erosions, immune cell infiltration, and colonic microvascular dysfunction, whereas the response of Phd2(f/+)Tie2:cre and Phd3(f/f)Tie2:cre mice to DSS was similar to that of their littermate controls. Using bone marrow chimeras and cell-specific cre mice, we demonstrated that ablation of Phd1 in haematopoietic cells but not in endothelial cells was both necessary and sufficient to inhibit experimental colitis. This effect relied, at least in part, on skewing of Phd1-deficient bone marrow-derived macrophages towards an anti-inflammatory M2 phenotype. These cells showed an attenuated nuclear factor-B-dependent response to lipopolysaccharide (LPS), which in turn diminished endothelial chemokine expression. In addition, Phd1 deficiency in dendritic cells significantly reduced interleukin-1 beta production in response to LPS. Taken together, our results further support the development of selective PHD1 inhibitors for ulcerative colitis, and identify haematopoietic cells as their primary target. Copyright (C) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
- Published
- 2016
5. Increased EPO Levels Are Associated With Bone Loss in Mice Lacking PHD2 in
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Rauner, Martina, Franke, Kristin, Murray, Marta, Singh, Rashim-Pal, Hiram-Bab, Sahar, Platzbecker, Uwe, Gassmann, Max, Socolovsky, Merav, Neumann, Drorit, Gabet, Yankel, Chavakis, Triantafyllos, Hofbauer, Lorenz-C., and Wielockx, Ben
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OSTEOCLAST ,Mice, Knockout ,purl.org/pe-repo/ocde/ford#3.02.18 [https] ,Erythropoietin/biosynthesis/genetics ,Osteoblasts/metabolism/pathology ,Bone Resorption/genetics/metabolism/pathology ,purl.org/pe-repo/ocde/ford#3.03.11 [https] ,Mice ,Bone Density/genetics ,Hypoxia-Inducible Factor-Proline Dioxygenases/deficiency ,BONE LOSS ,PHD2 ,Animals ,Osteoclasts/metabolism/pathology ,Hematopoietic Stem Cells/metabolism/pathology ,OSTEOBLAST ,Bone Marrow/metabolism/pathology ,ERYTHROPOIETIN - Abstract
The main oxygen sensor hypoxia inducible factor (HIF) prolyl hydroxylase 2 (PHD2) is a critical regulator of tissue homeostasis during erythropoiesis, hematopoietic stem cell maintenance, and wound healing. Recent studies point toward a role for the PHD2‐erythropoietin (EPO) axis in the modulation of bone remodeling, even though the studies produced conflicting results. Here, we used a number of mouse strains deficient of PHD2 in different cell types to address the role of PHD2 and its downstream targets HIF‐1α and HIF‐2α in bone remodeling. Mice deficient for PHD2 in several cell lineages, including EPO‐producing cells, osteoblasts, and hematopoietic cells (CD68:cre‐PHD2f/f) displayed a severe reduction of bone density at the distal femur as well as the vertebral body due to impaired bone formation but not bone resorption. Importantly, using osteoblast‐specific (Osx:cre‐PHD2f/f) and osteoclast‐specific PHD2 knock‐out mice (Vav:cre‐ PHD2f/f), we show that this effect is independent of the loss of PHD2 in osteoblast and osteoclasts. Using different in vivo and in vitro approaches, we show here that this bone phenotype, including the suppression of bone formation, is directly linked to the stabilization of the α‐subunit of HIF‐2, and possibly to the subsequent moderate induction of serum EPO, which directly influenced the differentiation and mineralization of osteoblast progenitors resulting in lower bone density. Taken together, our data identify the PHD2:HIF‐2α:EPO axis as a so far unknown regulator of osteohematology by controlling bone homeostasis. Further, these data suggest that patients treated with PHD inhibitors or EPO should be monitored with respect to their bone status.
- Published
- 2016
6. Loss of prolyl hydroxylase-2 in myeloid cells and T-lymphocytes impairs tumor development
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Mamlouk, Soulafa, Kalucka, Joanna, Singh, Rashim Pal, Franke, Kristin, Muschter, Antje, Langer, Anika, Jakob, Christiane, Gassmann, Max, Baretton, Gustavo B, Wielockx, Ben, University of Zurich, and Wielockx, Ben
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RNA, Messenger/genetics ,Antigens, CD/metabolism ,Apoptosis ,animal cell ,Myeloid Cells/immunology ,tumor-associated immune cells ,Immunoenzyme Techniques ,Mice ,Cell Movement ,purl.org/pe-repo/ocde/ford#3.02.21 [https] ,cytokine ,T lymphocyte ,prolylhydroxylase 2 ,1306 Cancer Research ,rat ,Oligonucleotide Array Sequence Analysis ,Mice, Knockout ,Cytokines/genetics ,Reverse Transcriptase Polymerase Chain Reaction ,article ,Flow Cytometry ,10081 Institute of Veterinary Physiology ,unclassified drug ,Hypoxia-Inducible Factor-Proline Dioxygenases/physiology ,cell death ,priority journal ,10076 Center for Integrative Human Physiology ,Disease Progression ,Antigens, Differentiation, Myelomonocytic/metabolism ,2730 Oncology ,enzyme deficiency ,Biomarkers, Tumor/genetics ,down regulation ,phenotype ,Blotting, Western ,animal experiment ,cancer genetics ,610 Medicine & health ,Real-Time Polymerase Chain Reaction ,cancer growth ,animal tissue ,Carcinoma, Lewis Lung/genetics ,Hypoxia-Inducible Factor 1, alpha Subunit/physiology ,Animals ,controlled study ,cell lineage ,mouse ,Bone Marrow/metabolism ,nonhuman ,Gene Expression Profiling ,animal model ,T-Lymphocytes/immunology ,ablation therapy ,cytokines ,oxygenase ,Mice, Inbred C57BL ,cell proliferation ,Melanoma, Experimental/genetics ,cancer size ,prolyl hydroxylase-2 ,570 Life sciences ,biology ,hematopoietic system ,Integrases/metabolism ,bone marrow cell - Abstract
The tumor microenvironment plays a pivotal role during cancer development and progression. The balance between suppressive and cytotoxic responses of the tumor immune microenvironment has been shown to have a direct effect on the final outcome in various human and experimental tumors. Recently, we demonstrated that the oxygen sensor HIF-prolyl hydroxylase-2 (PHD2) plays a detrimental role in tumor cells, stimulating systemic growth and metastasis in mice. In our current study, we show that the conditional ablation of PHD2 in the hematopoietic system also leads to reduced tumor volume, intriguingly generated by an imbalance between enhanced cell death and improved proliferation of tumor cells. This effect seems to rely on the overall downregulation of protumoral as well as antitumoral cytokines. Using different genetic approaches, we were able to confine this complex phenotype to the crosstalk of PHD2-deficient myeloid cells and T-lymphocytes. Taken together, our findings reveal a multifaceted role for PHD2 in several hematopoietic lineages during tumor development and might have important implications for the development of tumor therapies in the future. What's new? Here the authors describe the complex role of the oxygen sensor PHD2 in tumor-associated immune cells in a conditional PHD2-deficient mouse line. They demonstrate that the observed reduced tumor volume is a consequence of opposing changes including the drastic down-regulation of numerous pro- as well as anti-tumoral genes and an imbalance between enhanced cell death and greater proliferation of tumor cells. They confined this complex phenotype to the crosstalk of PHD2-deficient myeloid cells and T-lymphocytes. The findings reveal a multifaceted role for PHD2 in hematopoietic lineages during tumor development and might have important implications for the development of tumor therapies.
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- 2013
7. Erythropoietin Mediated Bone Loss in Mice Is Dose-Dependent and Mostly Irreversible.
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Kolomansky, Albert, Hiram-Bab, Sahar, Ben-Califa, Nathalie, Liron, Tamar, Deshet-Unger, Naamit, Mittelman, Moshe, Oster, Howard S., Rauner, Martina, Wielockx, Ben, Neumann, Drorit, and Gabet, Yankel
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BONES ,CANCELLOUS bone ,ERYTHROPOIETIN receptors ,ERYTHROPOIETIN ,DOSE-response relationship in biochemistry ,OSTEOCLASTOGENESIS ,MICE - Abstract
Recent studies have demonstrated that erythropoietin (EPO) treatment in mice results in trabecular bone loss. Here, we investigated the dose-response relationship between EPO, hemoglobin (Hgb) and bone loss and examined the reversibility of EPO-induced damage. Increasing doses of EPO over two weeks led to a dose-dependent increase in Hgb in young female mice, accompanied by a disproportionate decrease in trabecular bone mass measured by micro-CT (µCT). Namely, increasing EPO from 24 to 540 IU/week produced a modest 12% rise in Hgb (20.2 ± 1.3 mg/dL vs 22.7 ± 1.3 mg/dL), while trabecular bone volume fraction (BV/TV) in the distal femur decreased dramatically (27 ± 8.5% vs 53 ± 10.2% bone loss). To explore the long-term skeletal effects of EPO, we treated mice for two weeks (540 IU/week) and monitored bone mass changes after treatment cessation. Six weeks post-treatment, there was only a partial recovery of the trabecular microarchitecture in the femur and vertebra. EPO-induced bone loss is therefore dose-dependent and mostly irreversible at doses that offer only a minor advantage in the treatment of anemia. Because patients requiring EPO therapy are often prone to osteoporosis, our data advocate for using the lowest effective EPO dose for the shortest period of time to decrease thromboembolic complications and minimize the adverse skeletal outcome. [ABSTRACT FROM AUTHOR]
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- 2020
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8. PHD3 Acts as Tumor Suppressor in Mouse Osteosarcoma and Influences Tumor Vascularization via PDGF-C Signaling.
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Egners, Antje, Rezaei, Maryam, Kuzmanov, Aleksandar, Poitz, David M., Streichert, Doreen, Müller-Reichert, Thomas, Wielockx, Ben, and Breier, Georg
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CELL proliferation ,HYPOTHESIS ,SUBCUTANEOUS injections ,ANIMAL experimentation ,HYPOXEMIA ,TUMOR suppressor genes ,BLOOD-vessel tumors ,CELLULAR signal transduction ,LYMPHOKINES ,MICE ,OSTEOSARCOMA ,OXIDOREDUCTASES ,PLATELET-derived growth factor ,PROTEINS ,VASCULAR endothelial growth factors ,VASCULAR cell adhesion molecule-1 - Abstract
Cancer cell proliferation and insufficient blood supply can lead to the development of hypoxic areas in the tumor tissue. The adaptation to the hypoxic environment is mediated by a transcriptional complex called hypoxia-inducible factor (HIF). HIF protein levels are tightly controlled by oxygen-dependent prolyl hydroxylase domain proteins (PHDs). However, the precise roles of these enzymes in tumor progression and their downstream signaling pathways are not fully characterized. Here, we study PHD3 function in murine experimental osteosarcoma. Unexpectedly, PHD3 silencing in LM8 cells affects neither HIF-1α protein levels, nor the expression of various HIF-1 target genes. Subcutaneous injection of PHD3-silenced tumor cells accelerated tumor progression and was accompanied by dramatic phenotypic changes in the tumor vasculature. Blood vessels in advanced PHD3-silenced tumors were enlarged whereas their density was greatly reduced. Examination of the molecular pathways underlying these alterations revealed that platelet-derived growth factor (PDGF)-C signaling is activated in the vasculature of PHD3-deficient tumors. Silencing of PDGF-C depleted tumor growth, increased vessel density and reduced vessel size. Our data show that PHD3 controls tumor growth and vessel architecture in LM8 osteosarcoma by regulating the PDGF-C pathway, and support the hypothesis that different members of the PHD family exert unique functions in tumors. [ABSTRACT FROM AUTHOR]
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- 2018
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9. Hematopoietic Stem Cells but Not Multipotent Progenitors Drive Erythropoiesis during Chronic Erythroid Stress in EPO Transgenic Mice
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Beáta Ramasz, Ben Wielockx, Rashim Pal Singh, Andreas Dahl, Kristin Franke, Ian Henry, Triantafyllos Chavakis, Tatyana Grinenko, Mathias Lesche, Max Gassmann, University of Zurich, and Wielockx, Ben
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0301 basic medicine ,Myeloid ,1303 Biochemistry ,fate decision ,Biochemistry ,1309 Developmental Biology ,1307 Cell Biology ,Mice ,Erythropoiesis ,Erythroid Precursor Cells ,Hematopoietic stem cell ,10081 Institute of Veterinary Physiology ,Cell biology ,Haematopoiesis ,medicine.anatomical_structure ,10076 Center for Integrative Human Physiology ,erythropoietin ,Stem cell ,medicine.drug ,EPO-R ,bone marrow ,purl.org/pe-repo/ocde/ford#1.06.03 [https] ,Mice, Transgenic ,Biology ,Article ,03 medical and health sciences ,1311 Genetics ,Stress, Physiological ,Genetics ,medicine ,Animals ,Progenitor cell ,purl.org/pe-repo/ocde/ford#1.06.01 [https] ,progenitors ,transgenic ,hypoxia ,Gene Expression Profiling ,Computational Biology ,Cell Biology ,Hematopoietic Stem Cells ,030104 developmental biology ,Erythropoietin ,570 Life sciences ,biology ,hematopoietic stem cell ,Bone marrow ,purl.org/pe-repo/ocde/ford#1.06.07 [https] ,Developmental Biology ,EPO - Abstract
Summary The hematopoietic stem cell (HSC) compartment consists of a small pool of cells capable of replenishing all blood cells. Although it is established that the hematopoietic system is assembled as a hierarchical organization under steady-state conditions, emerging evidence suggests that distinct differentiation pathways may exist in response to acute stress. However, it remains unclear how different hematopoietic stem and progenitor cell subpopulations behave under sustained chronic stress. Here, by using adult transgenic mice overexpressing erythropoietin (EPO; Tg6) and a combination of in vivo, in vitro, and deep-sequencing approaches, we found that HSCs respond differentially to chronic erythroid stress compared with their closely related multipotent progenitors (MPPs). Specifically, HSCs exhibit a vastly committed erythroid progenitor profile with enhanced cell division, while MPPs display erythroid and myeloid cell signatures and an accumulation of uncommitted cells. Thus, our results identify HSCs as master regulators of chronic stress erythropoiesis, potentially circumventing the hierarchical differentiation-detour., Highlights • Chronic high EPO drives only HSCs to exhibit an exclusive erythroid progenitor profile • MPPs accumulate as uncommitted cells and display differential signatures, In this article, Wielockx and colleagues reveal that chronic erythropoietic stress induces distinct differences in the behavior of HSCs and their closely related MPPs. In particular, HSCs show greater commitment to an erythroid progenitor profile with heightened cell division, whereas MPPs are characterized by erythroid and immune signatures and an accumulation of uncommitted cells.
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- 2018
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10. HIF-1α is a protective factor in conditional PHD2-βdeficient mice suffering from severe HIF-2-induced excessive erythropoiesis
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Kathrin Geiger, Ben Wielockx, Guo-Hua Fong, Georg Breier, Vasuprada Iyengar, David M. Poitz, Max Gassmann, Gustavo B. Baretton, Joanna Kalucka, David R. Greaves, Teresa Otto, Alex M. Sykes, Alexander Weidemann, S. Bergmann, Steffen Jahn, Antje Muschter, Kristin Franke, Joachim Fandrey, Stefan R. Bornstein, Michael H. Muders, Rashim Pal Singh, Soulafa Mamlouk, Triantafyllos Chavakis, Kathrin Wieczorek, Tatsiana Ripich, University of Zurich, and Wielockx, Ben
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Keratinocytes ,Male ,1303 Biochemistry ,2720 Hematology ,Medizin ,nerve degeneration ,Kidney ,Severity of Illness Index ,Biochemistry ,1307 Cell Biology ,Nerve Degeneration/genetics ,Mice ,0302 clinical medicine ,Basic Helix-Loop-Helix Transcription Factors ,Cells, Cultured ,Mice, Knockout ,0303 health sciences ,heart sound p2 ,Polycythemia/genetics ,Neurodegeneration ,Hematopoiesis, Extramedullary/physiology ,Brain ,Hematology ,Kidney/cytology ,10081 Institute of Veterinary Physiology ,purl.org/pe-repo/ocde/ford#3.02.06 [https] ,Haematopoiesis ,medicine.anatomical_structure ,Hypoxia-inducible factors ,10076 Center for Integrative Human Physiology ,Hematopoiesis, Extramedullary ,030220 oncology & carcinogenesis ,Thrombocytopenia/genetics ,Erythropoiesis ,Female ,Procollagen-proline dioxygenase ,medicine.drug ,Hypoxia-Inducible Factor 1, alpha Subunit/genetics ,medicine.medical_specialty ,kidney ,mice ,Immunology ,Procollagen-Proline Dioxygenase ,610 Medicine & health ,Polycythemia ,Brain/physiology ,Biology ,Hypoxia-Inducible Factor-Proline Dioxygenases ,03 medical and health sciences ,Red Cells, Iron, and Erythropoiesis ,Procollagen-Proline Dioxygenase/genetics ,Internal medicine ,medicine ,protective factors ,Animals ,Humans ,Erythropoietin ,Transcription factor ,030304 developmental biology ,2403 Immunology ,Basic Helix-Loop-Helix Transcription Factors/genetics ,Keratinocytes/cytology ,Erythropoietin/genetics ,Cell Biology ,Fibroblasts ,Hypoxia-Inducible Factor 1, alpha Subunit ,medicine.disease ,Thrombocytopenia ,Erythrocytosis ,Mice, Inbred C57BL ,Endocrinology ,Fibroblasts/cytology ,Nerve Degeneration ,Cancer research ,570 Life sciences ,biology ,erythropoiesis - Abstract
Erythropoiesis must be tightly balanced to guarantee adequate oxygen delivery to all tissues in the body. This process relies predominantly on the hormone erythropoietin (EPO) and its transcription factor hypoxia inducible factor (HIF). Accumulating evidence suggests that oxygen-sensitive prolyl hydroxylases (PHDs) are important regulators of this entire system. Here, we describe a novel mouse line with conditional PHD2 inactivation (cKO P2) in renal EPO producing cells, neurons, and astrocytes that displayed excessive erythrocytosis because of severe overproduction of EPO, exclusively driven by HIF-2α. In contrast, HIF-1α served as a protective factor, ensuring survival of cKO P2 mice with HCT values up to 86%. Using different genetic approaches, we show that simultaneous inactivation of PHD2 and HIF-1α resulted in a drastic PHD3 reduction with consequent overexpression of HIF-2α-related genes, neurodegeneration, and lethality. Taken together, our results demonstrate for the first time that conditional loss of PHD2 in mice leads to HIF-2α–dependent erythrocytosis, whereas HIF-1α protects these mice, providing a platform for developing new treatments of EPO-related disorders, such as anemia.
- Published
- 2013
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