The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily that has multiple ligands and is implicated in the pathogenesis of various diseases, including diabetic complications, neurodegenerative disorders, and inflammatory responses. However, the role of RAGE in normal physiology is largely undefined. Here, we present evidence for a role of RAGE in osteoclast maturation and function, which has consequences for bone remodeling. Mice lacking RAGE had increased bone mass and bone mineral density and decreased bone resorptive activity in vivo. In vitro–differentiated RAGE-deficient osteoclasts exhibited disrupted actin ring and sealing zone structures, impaired maturation, and reduced bone resorptive activity. Impaired signaling downstream of αvβ3 integrin was observed in RAGE−/− bone marrow macrophages and precursors of OCs. These results demonstrate a role for RAGE in osteoclast actin cytoskeletal reorganization, adhesion, and function, and suggest that the osteosclerotic-like phenotype observed in RAGE knockout mice is due to a defect in osteoclast function.

High-mobility group box 1 (HMGB1), a nonhistone nuclear protein, is released by macrophages into the extracellular milieu consequent to cellular activation. Extracellular HMGB1 has properties of a pro-inflammatory cytokine through its interaction with receptor for advanced glycation endproducts (RAGE) and/or toll-like receptors (TLR2 and TLR4). Although HMGB1 is highly expressed in macrophages and differentiating osteoclasts, its role in osteoclastogenesis remains largely unknown. In this report, we present evidence for a function of HMGB1 in this event. HMGB1 is released from macrophages in response to RANKL stimulation and is required for RANKL-induced osteoclastogenesis in vitro and in vivo. In addition, HMGB1, like other osteoclastogenic cytokines (e.g., TNF␣), enhances RANKL-induced osteoclastogenesis in vivo and in vitro at subthreshold concentrations of RANKL, which alone would be insufficient. The role of HMGB1 in osteoclastogenesis is mediated, in large part, by its interaction with RAGE, an immunoglobin domain containing family receptor that plays an important role in osteoclast terminal differentiation and activation. HMGB1-RAGE signaling seems to be important in regulating actin cytoskeleton reorganization, thereby participating in RANKL-induced and integrin-dependent osteoclastogenesis. Taken together, these observations show a novel function of HMGB1 in osteoclastogenesis and provide a new link between inflammatory mechanisms and bone resorption.

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SUMMARY Neogenin has been identified as a receptor for neuronal axon guidance cues netrins and RGMs (repulsive guidance molecules). Here we provide evidence for neogenin in regulating endochondral bone development and BMP (bone morphogenetic protein) signaling. Neogenin deficient mice were impaired in digit/limb development and endochondral ossification. BMP2 induction of Smad1/5/8 phosphorylation and Runx2 expression, but not non-canonical p38 MAPK activation, was reduced in chondrocytes from neogenin mutant mice. BMP receptor association with membrane micro-domains, which is necessary for BMP signaling to Smad, but not p38 MAPK, was diminished in neogenin deficient chondrocytes. Furthermore, RGMs appear to mediate neogenin interaction with BMP receptors in chondrocytes. Taken together, our results indicate that neogenin promotes chondrogenesis in vitro and in vivo, revealing an unexpected mechanism underlying neogenin regulation of BMP signaling.

Neogenin, a deleted in colorectal cancer (DCC) family member, has been identified as a receptor for the neuronal axon guidance cues netrins and repulsive guidance molecules repulsive guidance molecules (RGM). RGMc, also called hemojuvelin (HJV), is essential for iron homeostasis. Here we provide evidence that neogenin plays a critical role in iron homeostasis by regulation of HJV secretion and bone morphogenetic protein (BMP) signaling.Livers of neogenin mutant mice exhibit iron overload, low levels of hepcidin, and reduced BMP signaling. Mutant hepatocytes in vitro show impaired BMP2 induction of Smad1/5/8 phosphorylation and hepcidin expression. Neogenin is expressed in liver cells in a reciprocal pattern to that of hepcidin, suggesting that neogenin functions in a cell nonautonomous manner. Further studies demonstrate that neogenin may stabilize HJV, a glycosylphosphatidylinositol-anchored protein that interacts with neogenin and suppresses its secretion. Taken together, our results lead the hypothesis that neogenin regulates iron homeostasis via inhibiting secretion of HJV, an inhibitor of BMP signaling, to enhance BMP signaling and hepcidin expression. These results reveal a novel mechanism underlying neogenin regulation of HJV-BMP signaling. IntroductionIron, a component of many metalloproteins, plays a crucial role in various physiologic processes, such as oxygen sensing and transport, mitochondrial electron transfer in the respiratory chain, and catalytic activity of diverse enzymes. Dysregulation of iron homeostasis leads to either iron deficiency, such as anemia, or iron overload characteristic of hereditary hemochromatosis, a relatively common inherited disorder associated with progressive organ dysfunction. 1 Cellular iron overload is toxic and causes cell death, at least in part due to free radical formation and lipid peroxidation.Hemojuvelin (HJV) is a member of a family of glycosylphosphatidylinositol (GPI)-linked cell surface proteins. It has an essential role in iron homeostasis. 2 HJV contains a putative N-terminal signal peptide, a tri-amino acid motif (the RGD site), a partial von Willebrand factor type D domain, and a C-terminal GPI anchor consensus sequence. 2,3 It is predominately expressed in the skeletal muscle, heart, and liver. 3,4 Mutations in the HJV gene is a leading cause of juvenile hemochromatosis, [5][6][7][8] and patients have low levels of hepcidin, 5,8 a crucial hormone secreted by the liver for iron homeostasis. HJV mutant mice exhibit reduced hepcidin expression and iron overload, 5,6 resembling patients with HJV mutations. Consistently, expression of HJV increases, while suppression of HJV decreases, hepcidin expression in cultured cells. 9 The mechanisms underlying HJV regulation of hepcidin expression and iron homeostasis are beginning to be elucidated. HJV was shown to function as a coreceptor for bone morphogenetic proteins (BMP). It binds to BMP2/4/6 and forms a complex with BMP receptors (type I and II). 10-12 HJV deficient mice/cells exhibit impaired BMP signaling ...

SUMMARY Rapsyn, an acetylcholine receptor (AChR)-interacting protein, is essential for synapse formation at the neuromuscular junction (NMJ). Like many synaptic proteins, rapsyn turns over rapidly at synapses. However, little is known about molecular mechanisms that govern rapsyn stability. Using a differential mass-spectrometry approach, we identified heat-shock protein 90β (HSP90β) as a component in surface AChR clusters. The HSP90β-AChR interaction required rapsyn and was stimulated by agrin. Inhibition of HSP90β activity or expression, or disruption of its interaction with rapsyn attenuated agrin-induced formation of AChR clusters in vitro and impaired the development and maintenance of the NMJ in vivo. Finally, we showed that HSP90β was necessary for rapsyn stabilization and regulates its proteasome-dependent degradation. Together, these results indicate a role of HSP90β in NMJ development by regulating rapsyn turnover and subsequent AChR cluster formation and maintenance.

The layer structure of graphene or reduced graphene oxide (rGO) opens an avenue for the development of advanced functional materials. In this paper, a MnCO3@rGO composite (MGC) was fabricated by anchoring MnCO3 nanoparticles (NPs) on rGO sheets in the hydrothermal reduction process of graphene oxide by using NaBH4. MnCO3 NPs with an average diameter of 8-20 nm were anchored onto the surface of rGO. The layer structure of rGO was maintained in MGC. The MGC was employed as an anode active material for lithium ion batteries. Excellent performances were obtained with a high specific capacity up to 857 mA·h·g(-1) after 100 cycles. The various charging-discharging current rates of 0.2-5.0 C exhibited no clear negative effect on the recycling stability of the MGC. The enhanced structure stability and ion and electron conductivity of the MGC are responsible for the superior electrochemical properties.

Rechargeable metal–sulfur batteries encounter severe safety hazards and fast capacity decay, caused by the flammable and shrinkable separator and unwanted polysulfide dissolution under elevated temperatures. Herein, a multifunctional Janus separator is designed by integrating temperature endurable electrospinning polyimide nonwovens with a copper nanowire‐graphene nanosheet functional layer and a rigid lithium lanthanum zirconium oxide‐polyethylene oxide matrix. Such architecture offers multifold advantages: i) intrinsically high dimensional stability and flame‐retardant capability, ii) excellent electrolyte wettability and effective metal dendritic growth inhibition, and iii) powerful physical blockage/chemical anchoring capability for the shuttled polysulfides. As a consequence, the as constructed lithium–sulfur battery using a pure sulfur cathode displays an outstandingly high discharge capacity of 1402.1 mAh g−1 and a record high cycling stability (approximately average 0.24% capacity decay per cycle within 300 cycles) at 80 °C, outperforming the state‐of‐the‐art results in the literature. Promisingly, a high sulfur mass loading of ≈3.0 mg cm−2 and a record low electrolyte/sulfur ratio of 6.0 are achieved. This functional separator also performs well for a high temperature magnesium–sulfur battery. This work demonstrates a new concept for high performance metal–sulfur battery design and promises safe and durable operation of the next generation energy storage systems.