Article

Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation

Department of Anesthesia, Harvard Medical School, Boston, MA, USA.
Blood (Impact Factor: 10.45). 03/2011; 117(18):4915-23. DOI: 10.1182/blood-2010-10-313064
Source: PubMed

ABSTRACT

Anemia of inflammation develops in settings of chronic inflammatory, infectious, or neoplastic disease. In this highly prevalent form of anemia, inflammatory cytokines, including IL-6, stimulate hepatic expression of hepcidin, which negatively regulates iron bioavailability by inactivating ferroportin. Hepcidin is transcriptionally regulated by IL-6 and bone morphogenetic protein (BMP) signaling. We hypothesized that inhibiting BMP signaling can reduce hepcidin expression and ameliorate hypoferremia and anemia associated with inflammation. In human hepatoma cells, IL-6-induced hepcidin expression, an effect that was inhibited by treatment with a BMP type I receptor inhibitor, LDN-193189, or BMP ligand antagonists noggin and ALK3-Fc. In zebrafish, the induction of hepcidin expression by transgenic expression of IL-6 was also reduced by LDN-193189. In mice, treatment with IL-6 or turpentine increased hepcidin expression and reduced serum iron, effects that were inhibited by LDN-193189 or ALK3-Fc. Chronic turpentine treatment led to microcytic anemia, which was prevented by concurrent administration of LDN-193189 or attenuated when LDN-193189 was administered after anemia was established. Our studies support the concept that BMP and IL-6 act together to regulate iron homeostasis and suggest that inhibition of BMP signaling may be an effective strategy for the treatment of anemia of inflammation.

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Available from: Paul Yu, Jan 22, 2016
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    • "Given that BMP antagonists promote the proliferation of BCs and their progeny in culture and that BMP signaling through Smad1/5/8 is downregulated during repair we asked whether giving LDN-193189 systemically after injury would enhance the regenerative process. Previous studies have used this compound to inhibit BMP signaling in vivo in mice (Steinbicker et al., 2011;Tsugawa et al., 2014;Yu et al., 2008) with positive effects on liver regeneration. We examined the potential effect of LDN in two ways; by counting epithelial cell number in the tracheas of treated mice versus controls (see later) and by quantifying the size of clones derived from lineage traced Krt5 BCs. "
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    ABSTRACT: The pseudostratified epithelium of the lung contains ciliated and secretory luminal cells and basal stem/progenitor cells. To identify signals controlling basal cell behavior we screened factors that alter their self-renewal and differentiation in a clonal organoid (tracheosphere) assay. This revealed that inhibitors of the canonical BMP signaling pathway promote proliferation but do not affect lineage choice, while exogenous BMP4 inhibits proliferation and differentiation. We therefore followed changes in BMP pathway components in vivo in the mouse trachea during epithelial regeneration from basal cells after injury. The findings suggest that BMP signaling normally constrains proliferation at steady state and this is break is released transiently during repair by the upregulation of endogenous BMP antagonists. Early in repair the packing of epithelial cells along the basal lamina increases, but density is later restored by active extrusion of apoptotic cells. Systemic administration of the BMP antagonist LDN-193189 during repair initially increases epithelial cell number but, following the shedding phase, normal density is restored. Taken together, these results reveal critical roles for both BMP signaling and cell shedding in homeostasis of the respiratory epithelium.
    Preview · Article · Jan 2016 · Development
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    • "Moreover, mice with a hepatocyte-specific knockout of Smad4 exhibit blunted hepcidin response to IL6 treatment (Wang et al., 2005). Importantly, BMP pathway inhibitors lower hepcidin, increase iron availability for erythropoiesis, and ameliorate anemia in animal models of anemia of inflammation (Theurl et al., 2011; Steinbicker et al., 2011b; Sun et al., 2013). "
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    ABSTRACT: Mutations in hemojuvelin (HJV) are the most common cause of the juvenile-onset form of the iron overload disorder hereditary hemochromatosis. The discovery that HJV functions as a co-receptor for the bone morphogenetic protein (BMP) family of signaling molecules helped to identify this signaling pathway as a central regulator of the key iron hormone hepcidin in the control of systemic iron homeostasis. This review highlights recent work uncovering the mechanism of action of HJV and the BMP-SMAD signaling pathway in regulating hepcidin expression in the liver, as well as additional studies investigating possible extra-hepatic functions of HJV. This review also explores the interaction between HJV, the BMP-SMAD signaling pathway and other regulators of hepcidin expression in systemic iron balance.
    Full-text · Article · May 2014 · Frontiers in Pharmacology
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    • "ACD is associated with significant morbidity and poor quality of life [5], and the amelioration of anemia may improve clinical outcomes of these patients. As it is often difficult to correct the underlying disease and currently available treatments have limited success, hepcidin-lowering agents [28,29], including K7174 or perhaps orally administrable K11706 [30], may be considered a new class of drugs in future. "
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    ABSTRACT: Hepcidin is the principal iron regulatory hormone, controlling the systemic absorption and remobilization of iron from intracellular stores. The expression of the hepcidin gene, HAMP, is increased in patients with anemia of chronic disease. Previously, the synthetic compound K7174 was identified through chemical screening as a novel inhibitor of the adhesion of monocytes to cytokine-stimulated endothelial cells. K7174 also ameliorated anemia induced by inflammatory cytokines in mice, which suggests a possible involvement of hepcidin regulation. The present study was performed to assess the impact of K7174 on hepcidin expression in a human hematoma cell line and in mice in vivo. We first demonstrated that K7174 treatment in HepG2 cells significantly decreased HAMP expression. Then, we conducted microarray analysis to determine the molecular mechanism by which K7174 inhibits HAMP expression. Transcriptional profiling confirmed the downregulation of HAMP. Surprisingly, we found that K7174 strongly induced GDF15, known as a negative regulator of HAMP expression. Western blotting analysis as well as ELISA confirmed the induction of GDF15 by K7174 treatment. Furthermore, K7174-mediated HAMP suppression was rescued by the silencing of GDF15 expression. Interestingly, we found that K7174 also upregulates CEBPB. Promoter analysis and chromatin immunoprecipitation analysis revealed that CEBPB could contribute to K7174-mediated transcriptional activation of GDF15. Subsequently, we also examined whether K7174 inhibits hepcidin expression in mice. Quantitative RT-PCR analysis with liver samples from K7174-treated mice demonstrated significant upregulation of Gdf15 and downregulation of Hamp expression, as compared to control mice. Furthermore, serum hepcidin concentration was also significantly decreased in K7174-treated mice. In conclusion, K7174 inhibits hepcidin expression partly by inducing GDF15. K-7174 may be a potential therapeutic option to treat anemia of chronic disease.
    Preview · Article · Sep 2013 · PLoS ONE
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