Oral administration of a bone morphogenetic protein type I receptor inhibitor prevents the development of anemia of inflammation

Mayeur, Claire; Kolodziej, Starsha; Wang, Amy; Xu, Xin; Lee, Arthur; Yu, Paul B.; Shen, John Paul; Bloch, Kenneth D.; Bloch, Donald B.

doi:10.3324/haematol.2014.111484

Cited by 32 publications

(25 citation statements)

References 17 publications

(9 reference statements)

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“…Rather, our in vivo observations suggest transcriptional synergy between these 2 signals and explain why lowering one of them using LDN-193189 or ALK3-Fc is sufficient to attenuate the induction of hepcidin gene expression by various inflammatory stimuli. [10][11][12] A similar attenuation is observed when BMP signaling is genetically impaired, as here in Bmp6 2/2 mice or in mice with liver-specific deletion of Alk3. 13 The present data are compatible with the previously proposed synergy between interleukin-6/STAT3 and BMP/SMAD signaling in regulating hepcidin.…”

supporting

confidence: 72%

Hepcidin upregulation by inflammation is independent of Smad1/5/8 signaling by activin B

Besson-Fournier

Gineste

Latour

et al. 2017

Blood

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Activin B, which is strongly induced by inflammatory stimuli in the mouse liver, has recently appeared as a potent inductor of hepcidin in vitro, via the crossactivation of noncanonical SMAD1/5/8 signaling. 1,2 To confirm the cause and effect relationships among activin B, Smad1/ 5/8 phosphorylation, and hepcidin in vivo, we challenged Inhbb 2/2 mice 3 (deficient in activin B) with lipopolysaccharide (LPS) or infected them with an Escherichia coli septicemic strain, as indicated in supplemental Methods (available on the Blood Web site).To examine whether, as observed in human hepatoma cell lines and in mouse primary hepatocytes, activin B also stimulates canonical SMAD2/3 and noncanonical SMAD1/5/8 signaling in vivo, we compared by western blot analysis Smad2 and Smad5 phosphorylation levels in the liver of wild-type and Inhbb 2/2 mice 4 hours after LPS stimulation ( Figure 1A) or E coli infection ( Figure 1B). Whereas these inflammatory stimuli strongly induce Smad2 and Smad5 phosphorylation in wild-type mice, none of these Smad effectors are activated in mice deficient in activin B. These data demonstrate that activin B, whose messenger RNA (mRNA) expression is strongly induced after LPS administration ( Figure 1C) or E coli infection ( Figure 1D), is required for activation of Smad1/5/8 signaling in these mice. In parallel to activating SMAD1/5/8 phosphorylation in vitro, activin B was also shown to induce hepcidin expression.1,2 Remarkably, pretreatment of hepatocytes with the BMP type I receptor inhibitor LDN-193189 prevented both the induction of SMAD/5/8 phosphorylation and the upregulation of the hepcidin (HAMP) gene expression by activin B, 1 suggesting that, at least in vitro, the effect of activin B on hepcidin expression was entirely attributable to the activation of noncanonical SMAD signaling. Since activin B also activates noncanonical Smad1/5/8 signaling in vivo, we expected that induction of hepcidin expression in response to LPS administration or E coli infection would be impaired in Inhbb 2/2 mice. However, the magnitude of hepcidin mRNA induction and its evolution over time was unexpectedly similar in wild-type and in Inhbb 2/2 mice challenged with LPS ( Figure 1E) or infected with E coli (Figure 1F), pointing out the limitations of in vitro studies. To confirm the data at the protein level, serum hepcidin was quantified by competitive enzyme-linked immunosorbent assay (ELISA) in wild-type and in Inhbb 2/2 mice before and 4 hours after a LPS challenge. As suggested by the quantitative polymerase chain reaction (PCR) data, and similarly to wild-type mice, Inhbb 2/2 mice produce on average 3 times more hepcidin after endotoxin administration ( Figure 1G). These results show that neither activation of Smad1/5/8 signaling nor activin B induction is necessary for upregulation of hepcidin production by inflammatory stimuli such as LPS administration or E coli infection.

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supporting

confidence: 72%

Hepcidin upregulation by inflammation is independent of Smad1/5/8 signaling by activin B

Besson-Fournier

Gineste

Latour

et al. 2017

Blood

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“…186,187 Mayeur and colleagues subsequently showed that oral administration of LDN-193189 was sufficient to prevent anaemia in this model of chronic inflammation. 188 Taken together, these observations suggest that inhibiting BMP signalling might represent a novel and practical therapeutic target for treating anemia of chronic disease.…”

Section: H1 Bmps and The Cardiovascular Systemmentioning

confidence: 96%

Targeting BMP signalling in cardiovascular disease and anaemia

et al. 2015

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Bone morphogenetic proteins (BMPs) and their receptors, known to be essential regulators of embryonal patterning and organogenesis, are also critical for the regulation of cardiovascular structure and function. In addition to their contributions to syndromic disorders of heart and vascular development, BMP signalling is increasingly recognized for its influence on endocrine-like functions in postnatal cardiovascular and metabolic homeostasis. In this Review, we discuss several critical and novel aspects of BMP signalling in cardiovascular health and disease, which highlight the cell- and context-specific nature of BMP signalling. Based on advancing knowledge of the physiological roles and regulation of BMP signaling, we indicate opportunities for therapeutic intervention in a range of cardiovascular conditions including atherosclerosis and pulmonary arterial hypertension, and well as for anaemia of chronic disease. Depending on the context and the repertoire of ligands and receptors involved in specific disease processes, the selective inhibition or enhancement of signaling via particular BMP ligands (such as in atherosclerosis and pulmonary arterial hypertension, respectively) might be beneficial. The development of selective small molecule antagonists of BMP receptors, and the identification of ligands selective for BMP receptor complexes expressed in the vasculature provide the most immediate opportunities for new therapies.

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“…A small molecule BMP type I receptor inhibitor (LDN-193189) [49;54-55] and a soluble hemojuvelin fusion protein [55-56] showed efficacy to lower hepcidin and mobilize iron in animal models of AI. Soluble hemojuvelin entered Phase 2 clinical trials to treat anemia in human patients with kidney disease (NCT02228655).…”

Section: Novel Therapeutic Strategies For Aimentioning

confidence: 99%

Hepcidin regulation in the anemia of inflammation

Wang

Babitt²

2016

Current Opinion in Hematology

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126

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Purpose of review Anemia is prevalent in patients with infections and other inflammatory conditions. Induction of the iron regulatory hormone hepcidin has been implicated in the pathogenesis of anemia of inflammation (AI). This review outlines recent discoveries in understanding how hepcidin and its receptor ferroportin are regulated, how they contribute to AI, and how this knowledge may help guide new diagnostic and therapeutic strategies for this disease. Recent findings IL6 is a primary driver for hepcidin induction in many models of AI, but the SMAD1/5/8 pathway also contributes, likely via Activin B and SMAD-STAT3 interactions at the hepcidin promoter. Hepcidin has an important functional role in many, but not all, forms of AI, although hepcidin-independent mechanisms also contribute. In certain populations, hepcidin assays may help target therapy with iron or erythropoiesis stimulating agents to patients who may benefit most. New therapies targeting the hepcidin-ferroportin axis have shown efficacy in pre-clinical and early clinical studies. Summary Recent studies confirm an important role for the hepcidin-ferroportin axis in the development of AI, but also highlight the diverse and complex pathogenesis of this disorder depending on the underlying disease. Hepcidin-based diagnostic and therapeutic strategies offer promise to improve anemia treatment, but more work is needed in this area.

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Oral administration of a bone morphogenetic protein type I receptor inhibitor prevents the development of anemia of inflammation

Cited by 32 publications

References 17 publications

Hepcidin upregulation by inflammation is independent of Smad1/5/8 signaling by activin B

Hepcidin upregulation by inflammation is independent of Smad1/5/8 signaling by activin B

Targeting BMP signalling in cardiovascular disease and anaemia

Hepcidin regulation in the anemia of inflammation

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