Bone morphogenetic protein (BMP) signaling induces hepatic expression of the peptide hormone hepcidin. Hepcidin reduces serum iron levels by promoting degradation of the iron exporter ferroportin. A relative deficiency of hepcidin underlies the pathophysiology of many of the genetically distinct iron overload disorders, collectively termed hereditary hemochromatosis. Conversely, chronic inflammatory conditions and neoplastic diseases can induce high hepcidin levels, leading to impaired mobilization of iron stores and the anemia of chronic disease. Two BMP type I receptors, Alk2 (Acvr1) and Alk3 (Bmpr1a), are expressed in murine hepatocytes. We report that liver-specific deletion of either Alk2 or Alk3 causes iron overload in mice. The iron overload phenotype was more marked in Alk3-than in Alk2-deficient mice, and Alk3 deficiency was associated with a nearly complete ablation of basal BMP signaling and hepci- IntroductionThe hepatic hormone hepcidin regulates serum iron levels in mice and humans by inducing degradation of the iron exporter, ferroportin. 1,2 Low ferroportin levels reduce intestinal iron absorption and the release of iron from macrophage stores. Human hereditary hemochromatosis is characterized by low hepcidin levels, leading to iron accumulation in liver, heart, and endocrine organs. 1,3 Similarly, hepcidin deficiency causes hepatic iron overload in mice. 2,4 In contrast, high hepcidin levels contribute to the anemia of chronic disease (ACD) by reducing iron bioavailability for erythropoiesis. 5,6 Recent studies have demonstrated a critical role for bone morphogenetic protein (BMP) signaling in the regulation of hepcidin expression by iron. [7][8][9][10][11] Binding of BMP ligands to type I and type II BMP receptors induces the type II receptor to phosphorylate and activate the type I receptor. The activated type I receptor, in turn, phosphorylates intracellular signaling molecules, including SMADs 1, 5, and 8. Phosphorylated SMADs 1, 5, and 8 bind SMAD4 and together translocate to the nucleus, where they activate the expression of genes, including hepcidin and the Id family of transcription factors. 12 Deficiency of Smad4, 10 the BMP coreceptor hemojuvelin, 13,14 or BMP6 15,16 in hepatocytes reduces expression of hepcidin 17,18 and induces iron overload. In addition, BMP signaling appears to have an important role in the induction of hepcidin expression by inflammatory mediators that are involved in ACD. 11,19,20 There are 4 type I BMP receptors: Alk1, Alk2, Alk3, and Alk6. The identity of the type I BMP receptor(s) responsible for iron-dependent signaling and the regulation of hepcidin expression in hepatocytes are unknown. Alk1 is predominantly expressed in the endothelium. Alk6 is expressed at low levels in murine liver, 21 and global Alk6 deficiency does not induce iron overload in mice (D. R. Campagna, P. J. Schmidt, and M.D.F., unpublished observations, January 2011). In contrast, Alk2 and Alk3 are abundantly expressed in hepatocytes. 21 To identify the type I BMP receptor required for th...

Obesity is associated with an increased incidence and severity of asthma, as well as other lung disorders, such as pulmonary hypertension. Adiponectin (APN), an antiinflammatory adipocytokine, circulates at lower levels in the obese, which is thought to contribute to obesity-related inflammatory diseases. We sought to determine the effects of APN deficiency in a murine model of chronic asthma. Allergic airway inflammation was induced in APN-deficient mice (APN(-/-)) using sensitization without adjuvant followed by airway challenge with ovalbumin. The mice were then analyzed for changes in inflammation and lung remodeling. APN(-/-) mice in this model develop increased allergic airway inflammation compared with wild-type mice, with greater accumulation of eosinophils and monocytes in the airways associated with elevated lung chemokine levels. Surprisingly, APN(-/-) mice developed severe pulmonary arterial muscularization and pulmonary arterial hypertension in this model, whereas wild-type mice had only mild vascular remodeling and comparatively less pulmonary arterial hypertension. Our findings demonstrate that APN modulates allergic inflammation and pulmonary vascular remodeling in a model of chronic asthma. These data provide a possible mechanism for the association between obesity and asthma, and suggest a potential novel link between obesity, inflammatory lung disease, and pulmonary hypertension.

Trace concentrations of polycyclic aromatic hydrocarbons (PAHs) have been successfully detected using surface-enhanced Raman scattering (SERS) spectroscopy. For such purpose, new SERS substrates have been developed, consisting of Ag nanoparticles, either in suspension or immobilized on glass, obtained by a new method and covered by adsorbed self-assembled calix[4]arene molecules. Among the assayed calix[4]arenes, the 25,27-dicarboethoxy-26,28-dihydroxy-p-tert-butylcalix[4]arene host molecule displays analytical selectivity to the PAH guest systems bearing four benzene rings, mainly pyrene. The host-guest interaction mechanism seems to take place through a π-π stacking interaction leading to a charge transfer between the complex and the metallic surface, which may also induce a notable influence on the surface charge of the metallic nanoparticle.

Epigenetic silencing of fragile X mental retardation 1 (FMR1) causes fragile X syndrome (FXS), a common inherited form of intellectual disability and autism. FXS correlates with abnormal synapse and dendritic spine development, but the molecular link between the absence of the FMR1 product FMRP, an RNA binding protein, and the neuropathology is unclear. We found that the messenger RNA encoding bone morphogenetic protein type II receptor (BMPR2) is a target of FMRP. Depletion of FMRP increased BMPR2 abundance, especially that of the full-length isoform that bound and activated LIM domain kinase 1 (LIMK1), a component of the noncanonical BMP signal transduction pathway that stimulates actin reorganization to promote neurite outgrowth and synapse formation. Heterozygosity for BMPR2 rescued the morphological abnormalities in neurons both in Drosophila and in mouse models of FXS, as did the postnatal pharmacological inhibition of LIMK1 activity. Compared with postmortem prefrontal cortex tissue from healthy subjects, the amount of full-length BMPR2 and of a marker of LIMK1 activity was increased in this brain region from FXS patients. These findings suggest that increased BMPR2 signal transduction is linked to FXS and that the BMPR2-LIMK1 pathway is a putative therapeutic target in patients with FXS and possibly other forms of autism.

Surface-enhanced Raman scattering (SERS) spectra of tryptophan (Trp) were obtained. A unique SERS spectrum of Trp, corresponding to the most stable conformation and orientation on the metal surface, is observed after a stabilization period. The Trp molecules interact with the surface through both the carboxylate and amino groups; the aliphatic moiety is close to the surface. The pyrrole ring of the indole moiety is farther from the surface than the benzene fragment. The observed spectra vary depending on both the preparation of the silver colloid and the aggregation time. The interpretation of the experimental results is supported by theoretical treatment of the molecule on the silver surface.

Key Points• Presence of either ActR2a or BMPR2 in hepatocytes is sufficient to maintain hepatic hepcidin gene expression and iron metabolism.• Deficiency of both BMP type II receptors in hepatocytes induces iron overload.Expression of hepcidin, the hepatic hormone controlling iron homeostasis, is regulated by bone morphogenetic protein (BMP) signaling. We sought to identify which BMP type II receptor expressed in hepatocytes, ActR2a or BMPR2, is responsible for regulating hepcidin gene expression. We studied Bmpr2 heterozygous mice (Bmpr2 1/2 ), mice with hepatocyte-specific deficiency of BMPR2, mice with global deficiency of ActR2a, and mice in which hepatocytes lacked both BMPR2 and ActR2a. Hepatic hepcidin messenger RNA (mRNA) levels, serum hepcidin and iron levels, and tissue iron levels did not differ in wild-type mice, Bmpr2 1/2 mice, and mice in which either BMPR2 or ActR2a was deficient.Deficiency of both BMP type II receptors markedly reduced hepatic hepcidin gene expression and serum hepcidin levels leading to severe iron overload. Iron injection increased hepatic hepcidin mRNA levels in mice deficient in either BMPR2 or ActR2a, but not in mice deficient in both BMP type II receptors. In addition, in mouse and human primary hepatocytes, deficiency of both BMPR2 and ActR2a profoundly decreased basal and BMP6-induced hepcidin gene expression. These results suggest that BMP type II receptors, BMPR2 and ActR2a, have redundant roles in the regulation of hepatic hepcidin gene expression and iron metabolism. (Blood. 2014;124(13):2116-2123

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Key Points Presence of the BMP type I receptor Alk3 is required for interleukin-6 to induce hepatic hepcidin gene expression. Alk3 contributes to the induction of hypoferremia by interleukin-6.