Projects
P1: Role of iron in bone metabolism of Hfe-hemochromatosis
PI: Maja Vujic Spasic (Ulm)
Team: Peter Steele-Perkins (PhD student)
Objective: unravel the iron vs. endocrine effects of Hfe-hemochromatosis on bone
One of the most common forms of genetic iron overload disorders (hereditary hemochromatosis, HH) in Caucasians is caused by mutations in the HFE gene. Most of the HFE-HH cases are explained by attenuated BMP/SMAD signaling activity in hepatocytes and subsequently low expression of the liver hormone hepcidin. Given that there is no active mechanism to excrete the excess of iron, progressive iron accumulation in various tissues occurs, causing multiple organ dysfunction and eventually failure, including liver cirrhosis, hepatocellular carcinoma, cardiomyopathies, diabetes, and hypogonadism. Clinical observations have raised attention to the possible correlation between iron overload and the development of osteoporosis in HH. However, some inconsistencies between the data exist as to whether iron per se affects bone integrity in HFE-HH patients. We hypothesize that osteoporosis in HFE-HH does not primarily arise from iron overload, as our most recent work showed that systemic iron overload, at the degree present in Hfe-/- mice, does not associate with microarchitectural impairment of bones, thus excluding a negative effect of iron overload on bone integrity. We suggest that potential triggers throughout the course of disease progression could induce malfunction in bones. A more simple explanation would be gonadal deficiency, a commonly known cause of bone loss, due to its co-occurrence with iron overload in HFE-HH. Whether iron overload in Hfe-/- mice may act as additional culprit when other osteoporosis triggers are present, such as liver cirrhosis and endocrine defects, is currently unknown and will be investigated here.
P2: 4-“T”-interplay (Type I BMP receptors/TFR1/TFR2/TMPRSS6) in iron sensing and bone homeostasis
PI: Andrea Steinbicker (Köln)
Team: Andrea Steinbicker (PI) & Guiscard Seebohm (PI); Isabelle Hornung (PhD student); Lisa Schrader (associated PostDoc); Anne Humberg (technician); Nathalie Strutz-Seebohm (Group leader)
Objective: elucidate effects of TMPRSS6 modulation on iron sensing and bone
The regulation of iron is crucial for liver and bone homeostasis. The transmembrane serine protease 6 (TMPRSS6) interacts with multiple components of the BMP signaling pathway including the BMP type I receptors ALK2 and ALK3, and thereby reduces the expression of the iron regulatory hormone hepcidin. Physiologically, hepcidin binds to and inactivates the iron exporter ferroportin if serum iron levels have reached sufficient levels. The loss of function mutation in TMPRSS6 causes iron-resistant-iron deficient anemia due to inappropriately high hepcidin levels. Even though aspects of TMPRSS6 binding and function in systemic iron homeostasis and liver regulation have been investigated, a detailed understanding of this regulatory system is elusive. The overall aim of this project is to investigate in depth signaling mechanisms and binding of TMPRSS6. Therefore, we will focus on the three main goals: 1) in silico-modeling and biochemistry of TMPRSS6 interactions with BMP receptors and the iron regulation proteins Hfe, Hjv, Tfr1, Tfr2, Kir2.1, Kv7.1, CaV2.1, 2) investigation of TMPRSS6 interactions with components of the BMP signaling pathway and other iron regulation proteins in vivo in mouse models, and 3) assessing the importance of TMPRSS6 in bone cells. In addition, we will investigate whether changes of systemic iron homeostasis impair the signaling mechanisms, which contributing factors occur, and how activation or blockage affects binding and receptor formation. This proposal will unravel mechanisms of TMPRSS6 actions in liver, iron sensing, and bone.
Team: Isabelle Hornung (PhD student); Fatemeh Eizadi Fard (PhD student); Lisa Schrader (associated PostDoc, Münster);
Objective: to increase our knowledge of the interplay of iron regulator proteins with TMPRSS6, as well as TFR1 and TFR2 with BMP signaling.
The goal of this proposal is to investigate the interplay of the 4 “T”s: the transmembrane serine protease 6 (TMPRSS6), transferrin receptor 1 (TFR1) and transferrin receptor 2 (TFR2) with the type I-bone morphogenetic protein receptors ALK2 and ALK3 in iron sensing and bone homeostasis. Structural modeling revealed interactions of TMPRSS6 with ALK2 and ALK3. Double hepatocyte specific Alk2/Tmprss6 deficient mice were generated and presented a phenotype similar to the iron overloaded hepatocyte-specific Alk2 deficiency, suggesting signaling of TMPRSS6 via ALK2. In addition, the interaction of the iron regulatory protein hemojuvelin with ALK2 and ALK3 was identified (Dogan et al., 2024). In our follow-up grant application, the overall goal is to increase the knowledge of the interplay of TMPRSS6, TFR1 and TFR2 with BMP signaling. We hypothesize that TMPRSS6, TFR2 and the bone morphogenetic protein receptors type I interact with each other to regulate iron homeostasis and that BMP type I receptors are essential for TMPRSS6, TFR1 and TFR2 to mediate their effect of iron increase and hepcidin modulation. We will generate the hepatocyte specific Tmprss6/Alk3 double knockout mouse to elucidate, if TMPRSS6 requires ALK3 for signaling. Second, the role of hepatic TFR1 in systemic iron homeostasis will be investigated by structural modeling in vitro as well as in hepatocyte specific Alk3 and Alk2 deficient mice by TFR1 overexpression in vivo. Third, we will elucidate the regulatory role of TFR2 in BMP signaling and hepcidin expression. TFR2 will be overexpressed in hepatocyte-specific Alk2, Alk3 and fourth, in Tmprss6 knockout mice to investigate the dependence of the 4 “T”s: TFR2, TFR1,TMPRSS6 and the type I BMP receptors ALK2 and ALK3. Bone analyses and proteomic analyses will be performed in all experiments (with TP3 and TP7).
P3: Deconstructing cell metabolic pathways causing iron toxicity-induced inhibition of osteoblast function, induction of FGF-23 and osteomalacia
PI: Martina Rauner (Dresden)
Team: Vanessa Passin (PhD student), Maria Ledesma-Colunga (associated PostDoc)
Objective: unravel the role of iron on osteoblast bioenergetics and the importance of Tfr1 for iron uptake in bone
Osteoblasts rely on a delicate balance of iron for proper differentiation and function. While iron is necessary for various cellular processes including DNA replication, proliferation, and cellular respiration, high levels of iron suppress osteoblast function. Despite this knowledge, our basic understanding on the impact of iron on osteoblasts remains very limited. To date, it is unclear how iron affects cellular functions in osteoblasts and what metabolic pathways are involved in regulating cell function. It is even unknown how iron enters into osteoblasts. In this project, we will decipher these unresolved aspects. We hypothesize that transferrin receptor 1 (Tfr1) is the main iron-uptake receptor in osteoblasts. Moreover, our preliminary data lead us to hypothesize that high concentrations of iron promote osteoblast proliferation at the expense of differentiation, thereby limiting bone formation. These hypotheses will be tested by investigating the bone phenotype of osteoblast-specific Tfr1 knockout mice. As osteoclasts play a major role in bone resorption and the role of Tfr1 has also not been addressed in vivo, we will also characterize osteoclast-specific Tfr1 knock-out mice. To address how iron is utilized by specific osteoblast subsets, we will use single-cell RNA sequencing, untargeted metabolomics, and functional tests in vitro to link metabolic profiles to specific osteoblast subsets and their function (e.g. proliferation vs. matrix production vs. matrix mineralization). This project will unravel the importance of Tfr1 for iron uptake in the skeleton and will provide detailed insights into the role of iron in osteoblast function and bioenergetics.
Team: Vanessa Passin (PhD student)
Objective: help to understand how iron affects osteoblast function and low bone mineralization and provide novel metabolic targets to prevent osteoblast insufficiency during iron overload conditions
Iron overload causes bone loss with increased bone resorption and decreased bone formation. Even though inhibited osteoblast function is a frequently reported observation in iron-induced bone loss, the mechanisms driving osteoblast inhibition beyond the induction of oxidative stress and ferroptosis are poorly understood. In the first funding period, we showed that loading bone cells with transferrin-bound iron is not detrimental for their differentiation and function. In line, knock-down of TFR1 did not impact bone cell function in vitro or in vivo, suggesting that other forms of iron such as non-transferrin bound iron have a negative impact on bone. In fact, treatment of osteoblasts with ferric ammonium citrate (FAC) profoundly decreased their differentiation, increased ROS production and lipid peroxidation. Metabolically, we found that FAC increased glycolysis and upregulated the expression of several enzymes necessary for the formation of lipids. Moreover, the anti-inflammatory and anti-oxidant metabolite itaconate was decreased after FAC treatment in osteoblasts in vitro and in the serum and bone of iron-treated mice. While iron treatment of mice led to an induction of FGF-23 levels and osteoid formation, an inhibition of bone formation, and a decrease in bone strength, treatment with the itaconate analog 4-octyl-itaconate (4OI) fully rescued all those parameters. 4OI treatment also fully rescued the iron-induced increase in lipid peroxidation in osteoblasts in vitro. As itaconate is a glycolysis inhibitor and rescued both, increased lipid peroxidation and FGF-23 levels, we hypothesize that iron metabolically reprograms osteoblasts to increase glycolysis to a) increase lipid peroxidation via stimulating the synthesis of lipids that are vulnerable to peroxidation and b) to induce FGF-23 levels and subsequent osteomalacia. We will test this hypothesis by treating osteoblasts and mice with iron with or without glycolysis inhibitors. Our main readouts will be oxidative stress and lipid analyses (peroxidation, lipid droplet formation, the lipidome profile), as well as FGF-23 levels and osteoid measurements. Moreover, besides inhibiting glycolysis, we plan to block enzymes critical for feeding into the lipid synthesis pathway. In summary, this project will help understand how iron affects osteoblast function and low bone mineralization and may provide novel metabolic targets to prevent osteoblast insufficiency during iron overload conditions.
P4: Defining the role of iron and iron regulators in ectopic ossification processes
PI: Ulrike Baschant (Dresden)
Team: Sven Spangenberg (PhD student)
Objective: dissect the role of Tfr2 in ossification
Heterotopic ossification (HO) is a process of ossification at abnormal anatomical sites. It is a common severe medical complication in patients after total hip replacement and it is a hallmark of the rare disease, fibrodysplasia ossificans progressiva. HO develops through a process of endochondral ossification involving stages of inflammation, chondrogenesis and osteogenesis. Mechanistically, BMP signaling has been implicated in the pathogenesis of HO. The BMP pathway is also an important regulator of iron homeostasis and we have recently shown that the iron regulator transferrin receptor 2 (Tfr2) regulates bone formation via the BMP-p38-MAPK pathway. Based on our discovery that the extracellular domain of Tfr2 (Tfr2-ECD) can bind BMP ligands and can be used as a ligand-trap to reduce HO, we hypothesize that Tfr2 plays a crucial role in the development of HO. Therefore, we aim to define the regulation of Tfr2 and its source in the various phases of HO by analyzing the inflammatory as well as the chondrogenic and osteogenic stages of HO in WT and Tfr2-/–mice. Furthermore, we will determine the role of iron and other iron regulators in HO in mice. To unravel the underlying mechanisms of Tfr2 and BMP downstream signaling in HO, we will subject conditional Tfr2-deficient mice as well as conditional mice specific for BMP signal transducers to HO. Moreover, we will define the BMP binding sites within the Tfr2-ECD and test the ability of shorter BMP-binding Tfr2-ECD fragments to block BMP-2-induced ossification in vivo. The project will provide novel insights into the impact of iron regulators on HO. Refining the ligand trap may provide a novel therapeutic approach to abrogate HO.
Team: Sven Spangenberg (PhD student)
Objective: to identify mechanisms such as dynamics and metabolic changes how iron affects heterotopic ossification & characterize the cell-intrinsic role of iron regulators such as TFR2 and others in HO formation
Heterotopic ossification (HO) is a process of bone formation in soft tissue. In the first funding period, we have identified that iron overload induced by high iron diet aggravates heterotopic bone formation in mice whereas iron-deficiency significantly reduced HO. Further, we found higher iron levels in heterotopic bone tissues from mice and in patients with advanced HO. Analyzing the early stages of HO revealed increased local inflammation in iron overloaded HO mice. Anti-inflammatory treatment with Dexamethasone or 4-octylitaconate effectively prevented the exacerbation of iron-induced aggravation of HO.We further found that iron regulators seem to be involved in the pathological process of HO formation as Tfr2-deficient mice show iron-independent effects on HO and as iron overloaded FpnC326S-mutant mice did not reveal increased HO. Tfr2 deficiency resulted in an elevated and more severe HO reflected by an increase of infiltrating pro-inflammatory cells in the early stages of HO. Based on these findings, we aim to unravel the underlying mechanisms of HO-induced aggravation of HO by evaluating reactive oxygen species production and metabolic changes in iron-induced aggravation of HO. We further aim to identify critical cell types accumulating iron and driving the process of HO formation. To determine the impact of intracellular iron dysbalance on HO, we will apply different Fpn mutant mice that are specifically intracellular iron depleted. To evaluate the intrinsic role of iron regulators in HO, we will subject different hemochromatosis mouse models within the consortium to HO and analyze the different stages of HO.
P5: Identification of iron-related signals controlling BMP expression in liver non-parenchymal cells
PI: Martina Muckenthaler (Heidelberg)
Team: Ruiyue Qiu (PostDoc), Stefania Cucinelli (PhD student), Anja Schuh (Clinician Scientist)
Objective: understanding liver cell crosstalk during iron sensing
Control of systemic iron homeostasis evolved to maintain a plasma iron concentration that secures adequate supplies to tissues and cells while preventing organ iron overload. The small hepatocyte-derived peptide hormone hepcidin synchronizes systemic iron fluxes to control the amount of iron available in the circulation for cellular iron uptake (e.g. in bone cells). Hepcidin targets the iron export protein ferroportin to trigger its degradation, thus preventing dietary iron absorption and macrophage iron release. A fundamental question in iron biology still remains unanswered: how are iron levels sensed by the liver? Hepcidin mRNA expression in hepatocytes is controlled by the BMP/Smad signaling pathway, whereby BMPs are expressed in liver non-parenchymal cells in response to changes in systemic iron levels. We hypothesize that a cross-talk of several liver cell types (hepatocytes, LSECs, stellate cells and Kupffer cells) will play a role for the hepcidin response to iron. By analyzing genetic mouse models of systemic iron overload and deficiency we will determine gene response patterns in all liver cell types and identify and validate pathways involved in the responses of BMPs to iron in primary cell (co) cultures. Additionally, we will test whether signals and pathways identified in the liver will also be operational in the bone for regulation of BMP levels.
Team: Ana Catarina Guilherme Pego (PostDoc); Stefania Cucinelli (PhD student)
Objective: to identify the hepatocyte-derived protein critical for iron-dependent BMP6 activation
Control of systemic iron homeostasis evolved to maintain a plasma iron concentration that secures adequate supplies to tissues and cells while preventing organ iron overload. The small hepatocyte-derived peptide hormone hepcidin synchronizes systemic iron fluxes to control the amount of iron available in the circulation for cellular iron uptake (e.g. in bone cells). Hepcidin targets the iron export protein ferroportin to trigger its degradation, thus preventing dietary iron absorption and macrophage iron release. A fundamental question in iron biology still remains to be addressed: how are iron levels sensed by the liver? Hepcidin mRNA expression in hepatocytes is controlled by the BMP/SMAD signaling pathway, whereby BMPs are expressed in liver non-parenchymal cells in response to changes in systemic iron levels. In the last funding period we filled important gaps in our understanding of hepcidin control and established that iron-dependent BMP6 responses in liver sinusoidal endothelial cells (LSECs) require a protein secreted from hepatocytes. By applying multi-approach strategies we will now aim to identify the hepatocyte-derived protein critical for iron-dependent BMP6 activation. We will generate Bmp6ScarLuc mice to increase the throughput of our experiments and to detect Bmp6 modulations in a time-resolved manner. In addition, by introducing the hepcidin-resistant ferroportin allele (FPNC326S) into murine LSECs and hepatocytes we will dissect the role of the cellular iron status for BMP6 control in vivo. Finally, we will identify the signaling pathways that mediate iron-dependent BMP6 responses in LSECs and their cross-talk to inflammation and oxidative stress. With this experimental approach we expect to gain detailed insight into how LSECs control BMP6 responses to ultimately determine systemic iron availability that is crucial for organ functions, including bone health.
P6: Molecular mechanisms of ferroportin-mediated protection against bone diseases
PI: Sandro Altamura (Heidelberg) & Lorenz Hofbauer (Dresden)
Team: Tiago Carvalho Oliveira (PhD student), Claudia Krause (technician)
Objective: dissect the role of Fpn in liver and bone
Iron balance is critical for bone health, and osteoporosis represents a frequent complication of iron overload disorders. Systemic iron homeostasis is maintained via the hepcidin/ferroportin (Fpn) system. Fpn mediates the release of iron from specialized iron-exporting cells such as duodenal enterocytes and splenic macrophages. Fpn levels, and thus the amount of iron exported, are post-translationally regulated by hepcidin, a hepatic hormone produced upon increased body iron levels that triggers Fpn internalization and degradation. Gain of function mutations of Fpn conferring resistance to hepcidin binding (FpnC326S) have been identified in patients with hereditary hemochromatosis type 4, characterized by an unrestricted systemic iron export that results in massive body iron overload. We have generated the FpnC326S knock-in mouse model of hereditary hemochromatosis type 4. As in the human disease, this model displays systemic iron overload and massive iron deposition in parenchymal tissues, including the liver. By contrast, cell types expressing Fpn are iron depleted due to hepcidin resistance. The central aim of this project is to identify the mechanisms whereby cell autonomous alteration in osteoblast and osteoclast iron content may affect bone remodeling and impair bone quality. Using customized mouse models of Fpn ablation (Fpn-ko) or stabilization (FpnC326S) specifically in osteoblasts and osteoclasts, we will address the following aims: (I) How do cell-specific alterations in bone iron content affect bone remodeling under normal and estrogen-deficient conditions? (II) How does Fpn prevent iron-related toxicity of osteoclasts/osteoblasts and impaired bone quality? (III) Which molecular patterns link imbalanced osteoblast/osteoclast iron content to altered bone remodeling and what are the translational consequences? This approach will allow us dissecting the component of the hormonal impairment from the cell-autonomous bone iron status in the pathogenesis of bone disorders.
Team: Tiago Carvalho Oliveira (PhD student), Claudia Krause (technician)
Objective: to investigate the molecular up-stream mechanisms whereby hypoxia alters FPN regulation in bone cells and how inflammatory cytokines modulate iron levels in bone tissue
Balanced iron levels are essential for bone health, as both iron deficiency and iron overload disorders frequently lead to complications like osteopenia and osteoporosis. Systemic iron homeostasis is regulated by the hepcidin/ferroportin (FPN) system. FPN mediates iron release from specialized iron-exporting cells, such as duodenal enterocytes and splenic macrophages. Hepcidin, a hepatic peptide hormone, regulates FPN levels post-translationally by inducing its internalization and degradation, thus controlling the amount of iron exported. FPN is also expressed in cells that lack a well-recognized role in iron handling, where it is hypothesized to act as a “safety valve” to prevent excessive iron accumulation. During the first funding period, we investigated the role of FPN in bone cells. By utilizing the gain-of-function FPN p.C326S mutation, which makes FPN resistant to hepcidin binding, we developed conditional mouse models with osteoclast- or osteoblast-specific iron deficiency. Our results revealed that FPN stabilization in osteoclasts leads to intracellular iron deficiency and Hypoxia Inducible Factor 2α (HIF2α) activation, resulting in increased bone resorption and bone loss. In contrast, FPN stabilization in osteoblasts, leading to iron deficiency, caused impaired osteoblastogenesis and reduced mineralization. These findings highlight the crucial role of FPN in maintaining bone homeostasis and suggest that cell-autonomous iron deficiency may contribute to bone loss diseases via distinct mechanisms. In the second funding period, we will test the hypothesis that hypoxia and inflammatory signals converge to regulate bone FPN expression and bone iron content, thereby contributing to altered bone remodeling. Specifically, we aim to investigate the molecular up-stream mechanisms whereby hypoxia alters FPN regulation in bone cells and how inflammatory cytokines modulate iron levels in bone tissue. These insights could pave the way for new therapeutic approaches targeting iron homeostasis to prevent bone diseases.
P7: Employing a systems biology approach to unravel organism-wide and hepatocyte-specific iron-dependent mechanisms regulating BMP signal transduction
PI: Ursula Klingmüller (Heidelberg)
Team: Philipp Kastl (PostDoc)
Objective: disentangle the interactions between signaling pathways of iron sensing and their effects on bone
Hepatocytes are the major cells for iron storage and secrete the iron regulator hepcidin. Expression of hepcidin is induced by the BMP/Smad signaling pathway. Transferrin receptor 2 (Tfr2) binds BMP ligands and BMP receptors, and activates Smad signaling, whereas TMPRSS6 cleaves BMP receptors and decreases BMP signal transduction. Additionally, hepcidin is an acute phase protein that is induced by IL-6 via the JAK1-STAT3 pathway. It was suggested that the IL-6/STAT and BMP/Smad axes interact at the transcription factor level, but the impact of this cross-talk on the dynamics of BMP signaling and on hepcidin expression in hepatocytes remains to be mechanistically resolved. To disentangle such complex interrelations, we will use a systems biology approach. With this approach we identified the three most relevant Smad complexes and predicted their impact on target gene expression. Based on a mathematical model of the IL-6/STAT3 signaling pathway, we predicted optimal inhibitor dosing to modulate the acute phase response including hepcidin expression. In our project we will address the communication between bone cells and hepatocytes ensuring iron homeostasis. By a mass spectrometric approach we will quantify the dynamics of plasma factors in response to iron overload in mouse models. Utilizing our integrative mathematical model of IL-6/BMP signal transduction and a targeted mass spectrometry approach, we will elucidate the impact of Tfr2 and of TMPRSS6 on the dynamics of hepcidin expression and will identify mechanisms regulating hepcidin expression that are altered in chronic liver diseases. The integrative approach that quantitatively dissects the communication between bone and liver and the regulation of iron homeostasis promises to identify novel strategies to prevent iron overload.
Team: Clara Hennersdorf (PhD student), Marcel Schilling (PostDoc)
Objective: to investigate sex-specific differences in the global interplay of molecular mechanisms regulating iron homeostasis and bone loss using mass spectrometry-based proteomics
Iron accumulation in the liver is a common precondition associated
with chronic liver diseases and has been linked with bone loss.
Complex, non-linear interrelations determine the regulation of iron
metabolism at multiple scales. In the first funding period, we
developed an integrated mathematical model of IL-6 and BMP signal
transduction, successfully predicting the dynamics of IL-6 induced
hepcidin expression, the main regulator of iron availability, in primary
human hepatocytes and HepG2 cells. The model identified that the
non-opioid analgesics Diclofenac (DCF) and Acetaminophen (APAP)
amplify IL-6 induced hepcidin expression in HepG2 cells by
modulating BMP receptor activation. Although many factors like ALK2,
ALK3, Hemojuvelin, and Transferrin receptor 2 (TFR2) have been
identified as regulators of hepcidin expression, the underlying
molecular mechanisms are only partially understood. For example, it
has been identified that transferrin receptor 1 (TFRC) and TFR2
influence BMP signal transduction by binding BMP ligands and
modulating SMAD, AKT, and MAPK pathways. We employed our
recently established proteomics pipeline and showed that iron
overloading in mice reduces the abundance of TFRC and TFR2 and
changes metabolic processes. In the second funding period, we will
study the impact of iron changes on the abundance of TFRC/TFR2
and on BMP signal transduction in iron-depleted or overloaded
primary murine hepatocytes stimulated with BMP-2 and -6 by
quantitative immunoblotting, global mass spectrometry and
phosphoproteomics. Since BMP-2 and -6 have different affinities for
ALK2 and ALK3, which trigger hepcidin expression to varying
degrees, we will explore if co-factors like TFR2, HJV and HFE
modulate ligand-receptor interaction in a comparable manner to DCF
and APAP. To investigate how this mechanism might be altered in
chronic liver disease, we will employ targeted proteomics to study
receptor complex composition and BMP-mediated hepcidin
expression in human hepatoma cells. Since we observed that the
human hepatoma cell line HepG2 secretes BMP ligands, we will determine by antibody-based assays the BMP ligand concentrations
in the plasma of mice with liver fibrosis. Chronic liver disease and
hepatocellular carcinoma are associated with a significantly increased
risk of bone fractures. We aim at testing the hypothesis that (i)
alterations in the regulation of iron metabolism are sex-specific, might
be (ii) indicative for progression of chronic liver disease and (iii) alter
the communication with the bone.
P8: Impact of iron overload and anemia on fractures
PI: Andrea Burden (Zürich), Andrea Steinbicker (Köln) & Lorenz Hofbauer (Dresden)
Team: Marcel Rauer (Clinician Scientist)
Objective: provide insights into the occurrence of fractures with iron disorders and their associated co-morbidities and co-medications
Anemia and osteoporosis are both frequent diseases and often coincide, especially among the aging population where low-grade inflammation is common. It has become evident that disturbances in iron metabolism are associated with bone disease. In addition, inflammation is a major cause of anemia and bone loss. Considering the clinical relevance of these diseases, the overall goal of this project is to investigate the mutual interactions between inflammation, iron homeostasis and bone metabolism in mice and men. To that end we will focus on determining the association of anemia/hemochromatosis and fractures in humans using the UK IQVIA Medical Research Database (IMRD). In preliminary analyses, we have shown that the cohort data is representative to the German population and that cohort analyses are feasible. A particular interest will be the analysis of co-morbidities, co-medication and fracture outcomes. Thus, this project will provide novel outcomes and insights into the occurrence of fractures with iron disorders and their associated co-morbidities and co-medications.
P9: Exploring TFR2 as a central hub of mitochondrial metabolism within the liver-bone-inflammation axis
PI: María Ledesma-Colunga (Dresden)