Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signalling

Rauner, Martina; Baschant, Ulrike; Roetto, Antonella; Pellegrino, Rosa Maria; Rother, Sandra; Salbach-Hirsch, Juliane; Weidner, Heike; Hintze, Vera; Campbell, Graeme; Petzold, A.; Lemaitre, Regis; Henry, Ian; Bellido, Teresita; Theurl, Igor; Altamura, Sandro; Colucci, Silvia; Muckenthaler, Martina U.; Schett, Georg; Komla-Ebri, Davide; Bassett, J. H. Duncan; Williams, Graham R.; Platzbecker, Uwe; Hofbauer, Lorenz C.

doi:10.1038/s42255-018-0005-8

Cited by 65 publications

(54 citation statements)

References 76 publications

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“…Moreover, BMP2 fails to activate the non-canonical AKT and ERK pathways in all the genotypes ( Online Supplementary Figure S7A, C-E ), likely because of their fast kinetics. 9 Surprisingly, BMP2 induces p38 phosphorylation only in Tfr2 -KO mice ( Figure 2D ), a process that in turn might increase SMAD1/5/8 phosphorylation, as shown in other cell types. 14 We speculate that in vivo Tfr2 deficiency enhances BMP2-mediated hepcidin expression through p38 phosphorylation.…”

mentioning

confidence: 65%

“…It interacts with HFE and TFR2 and is functionally independent of BMP6 and likely of ALK2. 1 Recent studies imply a function of HH proteins in BMP2- ALK3 signaling: both HJV 8 and TFR2 9 interact with BMP2, and TFR2 and HFE bind ALK3 9 , 10 ( data not shown ). However, the functional role of the HH proteins in BMP2-mediated hepcidin regulation is still elusive.…”

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confidence: 91%

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Hemochromatosis proteins are dispensable for the acute hepcidin response to BMP2

Pagani¹,

Pettinato²,

Colucci

et al. 2020

haematol

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confidence: 65%

mentioning

confidence: 91%

Hemochromatosis proteins are dispensable for the acute hepcidin response to BMP2

Pagani¹,

Pettinato²,

Colucci

et al. 2020

haematol

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“…24 The current study, using Biacore, shows that the direct BMP6-ERFE interaction is of high affinity (;1.17 nM), which contrasts with the estimated lower affinity of a TfR2-BMP interaction (;400 nM). 46 The development of anti-ERFE antibodies was also used as a tool to further investigate the ERFE mechanism of action. Using HTRF as a competition assay between anti-ERFE mAbs and BMP6, we show that BMP6 binds to a region of ERFE contained within the N-terminal domain ( Figure 3B).…”

Section: Discussionmentioning

confidence: 99%

Antibodies against the erythroferrone N-terminal domain prevent hepcidin suppression and ameliorate murine thalassemia

Arezes

Foy

McHugh

et al. 2020

Blood

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Erythroferrone (ERFE) is produced by erythroblasts in response to erythropoietin (EPO) and acts in the liver to prevent hepcidin stimulation by BMP6. Hepcidin suppression allows for the mobilization of iron to the bone marrow for the production of red blood cells. Aberrantly high circulating ERFE in conditions of stress erythropoiesis, such as in patients with β-thalassemia, promotes the tissue iron accumulation that substantially contributes to morbidity in these patients. Here we developed antibodies against ERFE to prevent hepcidin suppression and to correct the iron loading phenotype in a mouse model of β-thalassemia [Hbb(th3/+) mice] and used these antibodies as tools to further characterize ERFE’s mechanism of action. We show that ERFE binds to BMP6 with nanomolar affinity and binds BMP2 and BMP4 with somewhat weaker affinities. We found that BMP6 binds the N-terminal domain of ERFE, and a polypeptide derived from the N terminus of ERFE was sufficient to cause hepcidin suppression in Huh7 hepatoma cells and in wild-type mice. Anti-ERFE antibodies targeting the N-terminal domain prevented hepcidin suppression in ERFE-treated Huh7 cells and in EPO-treated mice. Finally, we observed a decrease in splenomegaly and serum and liver iron in anti–ERFE-treated Hbb(th3/+) mice, accompanied by an increase in red blood cells and hemoglobin and a decrease in reticulocyte counts. In summary, we show that ERFE binds BMP6 directly and with high affinity, and that antibodies targeting the N-terminal domain of ERFE that prevent ERFE–BMP6 interactions constitute a potential therapeutic tool for iron loading anemias.

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“…Sh3bp4 thus represents a new osteoarthritis susceptibility gene, the deletion of which accelerates joint damage. Its role in disease pathogenesis may involve the key TfR, FGFR, mTOR and Wnt signalling pathways, which regulate bone and cartilage homeostasis and tissue repair [47][48][49][50] .…”

Section: Early Onset Osteoarthritis In Bhlhe40 -/And Sh3pb4 -/Mutant mentioning

confidence: 99%

Accelerating functional gene discovery in osteoarthritis

Butterfield

Curry

Steinberg

et al. 2019

Preprint

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Osteoarthritis causes debilitating pain and disability, resulting in a huge socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in unselected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we generate mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by Crispr/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. This expanding resource of unselected mutant mice will transform the field by accelerating functional gene discovery in osteoarthritis and offering unanticipated drug discovery opportunities for this common and incapacitating chronic disease.

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Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signalling

Cited by 65 publications

References 76 publications

Hemochromatosis proteins are dispensable for the acute hepcidin response to BMP2

Hemochromatosis proteins are dispensable for the acute hepcidin response to BMP2

Antibodies against the erythroferrone N-terminal domain prevent hepcidin suppression and ameliorate murine thalassemia

Accelerating functional gene discovery in osteoarthritis

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