The many ways of osteoclast activation

• Text
• PDF

Abstract

Osteoclasts are the cells responsible for bone resorption, a process that is essential for the maintenance of healthy bones. Bone diseases, such as osteoporosis, which are characterized by high rates of bone resorption and loss of bone mass, may benefit from treatments that inhibit osteoclast formation and/or function. The RANKL/RANK pathway is critical for both osteoclast formation and function, and these effects are thought to be mediated by the transcription factor nuclear factor of activated T cells, cytoplasmic 1 (NFATc1). In this issue of the JCI, Bae et al. challenge the convention that NFATc1 is the sole critical regulator of RANKL/RANK-dependent osteoclast activation. Specifically, the authors show that MYC drives metabolic reprogramming in osteoclasts and that MYC induces estrogen receptor–related receptor α (ERRα) to regulate osteoclastogenesis. Importantly, both loss of MYC and pharmacological inhibition of ERRα attenuated bone loss in a mouse model of osteoporosis. Together, the results of this study suggest that the MYC/ERRα pathway should be further explored as a drug target for bone diseases.

Authors

Joseph Lorenzo

Sugar makes neutrophils RAGE: linking diabetes-associated hyperglycemia to thrombocytosis and platelet reactivity

• Text
• PDF

Abstract

Diabetes mellitus is associated with an increased risk for cardiovascular disease, but the link between hyperglycemia and atherothrombotic disease is not completely understood. Patients with diabetes often show hyporesponsiveness to antiplatelet therapies, and it has been suggested that hyperreactive reticulated platelets underlie this altered therapeutic response. In this issue of the JCI, Kraakman et al. uncover a previously unknown link between hyperglycemia and enhanced platelet production and reactivity. The authors demonstrate that high blood glucose levels trigger neutrophil release of S100 calcium-binding protein A8/A9 (S100A8/A9), which binds to the receptor for advanced glycation end products (RAGE) on Kupffer cells, ultimately leading to increased thrombopoietin (TPO) production in the liver. TPO causes megakaryocyte proliferation and increased platelet production. This study demonstrates the importance of glycemic control and identifies potential therapeutic targets in the normalization of platelet numbers and function in diabetes.

Authors

Robert H. Lee, Wolfgang Bergmeier

The SO(H)L(H) “O” drivers of oocyte growth and survival but not meiosis I

• Text
• PDF

Abstract

The spermatogenesis/oogenesis helix-loop-helix (SOHLH) proteins SOHLH1 and SOHLH2 play important roles in male and female reproduction. Although previous studies indicate that these transcriptional regulators are expressed in and have in vivo roles in postnatal ovaries, their expression and function in the embryonic ovary remain largely unknown. Because oocyte differentiation is tightly coupled with the onset of meiosis, it is of significant interest to determine how early oocyte transcription factors regulate these two processes. In this issue of the JCI, Shin and colleagues report that SOHLH1 and SOHLH2 demonstrate distinct expression patterns in the embryonic ovary and interact with each other and other oocyte-specific transcription factors to regulate oocyte differentiation. Interestingly, even though there is a rapid loss of oocytes postnatally in ovaries with combined loss of Sohlh1 and Sohlh2, meiosis is not affected and proceeds normally.

Authors

T. Rajendra Kumar

A SMAP in the face for cancer

• Text
• PDF

Abstract

Observed deficits in protein phosphatase 2A (PP2A) function in a variety of human cancers have stimulated drug discovery efforts aimed at restoring PP2A function to inhibit tumor growth. Work published by Sangodkar et al. in this issue of the JCI describes the characterization of orally available small molecule activators of PP2A (SMAPs). These SMAPs attenuated mitogenic signaling and triggered apoptosis in KRAS-mutant lung cancer cells and inhibited tumor growth in murine models. Tumors with mutations in the SMAP-binding site of the PP2A A subunit displayed resistance to SMAPs. Future studies that identify the PP2A-regulated events targeted by SMAPs should guide critical decisions about which cancers might be best treated with these molecules. This study provides encouraging evidence in favor of SMAPs as potential anticancer drugs.

Authors

Shirish Shenolikar

Defects in DNA replication hit NK cells and neutrophils

• Text
• PDF

Abstract

Patients who present with unique immunological phenotypes provide an opportunity to better understand defect-driving mutations. In this issue of the JCI, Cottineau and colleagues characterize 5 individuals who exhibited growth restriction, facial deformities, and a history of bacterial and viral infection. Further characterization revealed that these patients were neutropenic and NK cell deficient. These phenotypes were unexpectedly linked to mutations in the gene encoding a subunit of the Go-Ichi-Ni-San (GINS) complex, which is essential for DNA replication prior to cell division. Together, the results of this study lay the groundwork for future studies to explore the role of DNA replication in immune cell generation and function.

Authors

Klaus Ley

An indirect route to repetitive actions

• Text
• PDF

Abstract

It is increasingly evident that there is a genetic contribution to autism spectrum disorders (ASDs) and other neural disorders involving excessive repetition of action sequences. Among the implicated genes in these disorders are those encoding postsynaptic scaffolding proteins with roles in synaptic transmission and plasticity. Several mouse models harboring synonymous mutations have shown alterations in synaptic transmission within the striatum, which has key roles in controlling actions and action sequences. In this issue of the JCI, Wang and coworkers show that glutamatergic synaptic transmission onto striatal projection neurons is weakened in mutant mice lacking the SH3 and multiple ankyrin repeat domains 3 (SHANK3B) scaffolding protein, defective expression of which has been implicated in ASDs. This synaptic alteration gives rise to stronger activity in the indirect pathway accompanied by decreased dendritic spines on the indirect pathway medium spiny projection neuron, indicative of decreased numbers of glutamatergic synapses. Selectively enhancing activity in this pathway reduced excessive repetitive grooming in the mutant mice. Changes in glutamatergic input to striatal projection neurons have been observed in several other murine ASD models and associated disorders. Thus, manipulation of the function of the striatal indirect pathway may be a useful therapeutic target for treating disorders characterized by excessive repetitive behaviors.

Authors

David M. Lovinger

Access granted: iRGD helps silicasome-encased drugs breach the tumor barrier

• Text
• PDF

Abstract

In this issue of the JCI, Liu et al. use irinotecan-loaded nanoparticles to treat pancreatic adenocarcinomas in mice. Encapsulating drugs into nanoparticles has distinct advantages: it can improve the pharmacokinetics of the drug, enhance efficacy, and reduce unwanted side effects. A drawback is that the large size of nanoparticles restricts their access to the tumor interior. Liu and colleagues show that the cyclic tumor-penetrating peptide iRGD, reported to be capable of enhancing tumor penetration by drugs, can overcome this limitation to a substantial degree when administered together with the nanoparticles. Pancreatic adenocarcinoma is a challenging malignancy to treat and in desperate need for improved treatments; therefore, advances like this are most welcome.

Authors

Erkki Ruoslahti

Salt and water: not so simple

• Text
• PDF

Abstract

It has long been viewed that the maintenance of osmotic balance in response to high salt intake is a passive process that is mediated largely by increased water consumption to balance the salt load. Two studies in this issue of the JCI challenge this notion and demonstrate that osmotic balance in response to high salt intake involves a complex regulatory process that is influenced by hormone fluctuation, metabolism, food consumption, water intake, and renal salt and water excretion. Rakova et al. report the unexpected observation that long-term high salt intake did not increase water consumption in humans but instead increased water retention. Moreover, salt and water balance was influenced by glucocorticoid and mineralocorticoid fluctuations. Kitada et al. extend upon these findings in mouse models and determined that increased urea and a corresponding increase in urea transporters in the renal medulla as the result of increased protein intake promote the water retention that is needed to achieve osmotic homeostasis. Together, the results of these two studies lay the groundwork for future studies to determine how, in the face of chronic changes in salt intake, humans maintain volume and osmotic homeostasis.

Authors

Mark L. Zeidel

PD-L1 serves as a double agent in separating GVL from GVHD

• Text
• PDF

Abstract

Allogeneic hematopoietic cell transplantation (HCT) represents a potentially curative treatment for a variety of hematologic malignancies due to the well-recognized graft-versus-leukemia/lymphoma (GVL) effect that is mediated by donor-derived alloreactive T cells. However, graft-versus-host disease (GVHD) is mediated by the same T cells and remains a significant clinical problem associated with substantial morbidity and mortality. In this issue of the JCI, Ni and colleagues used several murine models of GVHD to evaluate the effect of CD4⁺ T cell depletion on GVL versus GVHD and revealed that depletion of CD4⁺ T cells leads to the upregulation of PD-L1 by recipient tissues and donor CD8⁺ T cells. Interaction of PD-L1 with PD-1 in GVHD-targeted tissues resulted in CD8⁺ T cell exhaustion and apoptosis, thereby preventing GVHD, whereas PD-L1 interactions with CD80 in lymphoid tissue promoted CD8⁺ T cell survival and expansion, thereby enhancing the GVL response. By separating these seemingly similar alloreactive T cell responses based on the context of interaction, the results of this study may lay the groundwork for the development of effective clinical strategies to enhance GVL while minimizing GVHD following allogeneic HCT.

Authors

Todd V. Brennan, Yiping Yang

T cells take directions from supporting cast in graft-versus-host disease

• Text
• PDF

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only treatment option for several severe hematological malignancies. The development of graft-versus-host disease (GVHD) is a common complication of the procedure and results when donor T cells become activated against recipient-specific antigens. The factors that drive the alloreactive T cell response are not completely understood. In this issue of the JCI, Chung and colleagues present evidence that stromal cells within lymphoid tissue express the Notch ligands Delta-like 1/4 (DLL1 and DLL4), which in turn directly activate T cells. Importantly, inhibition of DLL1/DLL4-mediated Notch signaling in murine HSCT models dramatically reduced GVHD and improved graft survival.

Authors

Derk Amsen

Resisting fatal attraction: a glioma oncometabolite prevents CD8⁺ T cell recruitment

• Text
• PDF

Abstract

Immunotherapy has emerged as a potent approach for treating aggressive cancers, such as non–small-cell lung tumors and metastatic melanoma. Clinical trials are now in progress for patients with malignant gliomas; however, a better understanding of how these tumors escape immune surveillance is required to enhance antitumor immune responses. With gliomas, the recruitment of CD8+ T cells to the tumor is impaired, in part preventing containment or elimination of the tumor. In this issue of the JCI, Kohanbash and colleagues present an elegant dissection of how gliomas exploit an enzymatic activity acquired through a common mutation to abrogate the migration of CD8+ T cells to the tumor. They show that the oncometabolite 2-hydroxyglutarate (2HG), generated by mutated forms of isocitrate dehydrogenase (IDH1 and IDH2), reduces the expression of STAT1, thereby limiting the production of the chemokines CXCL9 and CXCL10. As a result, IDH1-mutated tumors are less effectively infiltrated by CD8+ T cells, contributing to tumor escape. Finally, in mice harboring syngeneic gliomas, an inhibitor of 2HG synthesis complemented vaccination to ameliorate tumor control. Understanding how to increase immune infiltration of gliomas represents a key first step in achieving tumor destruction through immunotherapy.

Authors

Liliana E. Lucca, David A. Hafler

A “tail” of opioid receptor variants

• Text
• PDF

Abstract

Opioids are the gold-standard treatment for severe pain. However, potentially life-threatening side effects decrease the safety and effectiveness of these compounds. The addiction liability of these drugs has led to the current epidemic of opioid abuse in the US. Extensive research efforts have focused on trying to dissociate the analgesic properties of opioids from their undesirable side effects. Splice variants of the mu opioid receptor (MOR), which mediates opioid actions, have unique pharmacological properties and anatomic distributions that make them attractive candidates for therapeutic pain relief. In this issue of the JCI, Xu et al. show that specific C-terminal regions of the MOR can modulate side effects without altering analgesia. This discovery greatly improves our understanding of opioid side effects and suggests intriguing therapeutic approaches that could improve both the safety and long-term effectiveness of opioids.

Authors

Stephanie Puig, Howard B. Gutstein

Building discontinuous liver sinusoidal vessels

• Text
• PDF

Abstract

Blood vessels have a unified mission to circulate blood throughout the body; however, they have additional diverse and specialized roles in various organs. For example, in the liver, discontinuous sinusoids, which are fenestrated capillaries with intercellular gaps and a fragmented basement membrane, facilitate delivery of macromolecules to highly metabolic hepatocytes. During embryonic development, discontinuous sinusoids also allow circulating hematopoietic progenitor and stem cells to populate the liver and promote blood cell differentiation. In this issue of the JCI, Géraud et al. describe an essential role for the transcription factor GATA4 in promoting the development of discontinuous sinusoids. In the absence of liver sinusoidal GATA4, mouse embryos developed hepatic capillaries with upregulated endothelial cell junction proteins and a continuous basement membrane. These features prevented hematopoietic progenitor cells from transmigrating into the developing liver, and Gata4-mutant embryos died from subsequent liver hypoplasia and anemia. This study highlights the surprising and extensive transcriptional control GATA4 exercises over specialized liver vascular development and function.

Authors

Courtney T. Griffin, Siqi Gao

DREADDing proglucagon neurons: a fresh look at metabolic regulation by the brain

• Text
• PDF

Abstract

Glucagon-like peptide 1 receptor (GLP-1R) signaling in the CNS has been linked to reduced food intake, lower body weight, improved glucose homeostasis, and activation of CNS stress axes. GLP-1 is produced by cells that express proglucagon (GCG); however, the stimuli that activate GCG⁺ neurons are not well known, which has made understanding the role of this neuronal population in the CNS a challenge. In this issue of the JCI, Gaykema et al. use designer receptors exclusively activated by designer drugs (DREADD) technology to specifically activate GCG⁺ neurons in mouse models. While activation of GCG⁺ neurons did reduce food intake, and variably decreased hepatic glucose production, other GLP-1–associated effects were not observed — e.g., activation of stress axes or stimulation of insulin secretion — in response to GCG⁺ neuron activation. The authors have provided a valuable model to study this set of neurons in vivo, and their results provide new insights into the function of GCG⁺ neural activity in the brain and raise questions that will move research on this clinically relevant neural system forward.

Authors

Jonathan E. Campbell, David A. D’Alessio

MicroRNA-7a2 suppression causes hypogonadotropism and uncovers signaling pathways in gonadotropes

• Text
• PDF

Abstract

MicroRNAs (miRNAs) have emerged as important regulators of a variety of biological processes and pathways. In this issue of the JCI, Ahmed et al. reveal that miR-7a2 is a critical regulator of sexual maturation and reproductive function, as mice lacking miR-7a2 develop hypogonadotropic hypogonadism and infertility. Using a bioinformatics approach, the authors identified several miR-7a2 target genes and pathways that have not been previously associated with gonadotropin biosynthesis and/or secretion. Together, these results identify miR-7a2–regulated genes involved in reproductive hormone biosynthesis pathways and provide a framework for future studies aimed at understanding rare reproductive conditions.

Authors

William F. Crowley, Ravi Balasubramanian

Muscular dystrophy meets protein biochemistry, the mother of invention

• Text
• PDF

Abstract

Muscular dystrophies result from a defect in the linkage between the muscle fiber cytoskeleton and the basement membrane (BM). Congenital muscular dystrophy type MDC1A is caused by mutations in laminin α2 that either reduce its expression or impair its ability to polymerize within the muscle fiber BM. Defects in this BM lead to muscle fiber damage from the force of contraction. In this issue of the JCI, McKee and colleagues use a laminin polymerization–competent, designer chimeric BM protein in vivo to restore function of a polymerization-defective laminin, leading to normalized muscle structure and strength in a mouse model of MDC1A. Delivery of such a protein to patients could ameliorate many aspects of their disease.

Authors

Steven D. Funk, Jeffrey H. Miner

Seeing how we smell

• Text
• PDF

Abstract

PET allows noninvasive imaging of a variety of events in the body, including the activity of neuronal circuits in the brain that are involved in cognition and behaviors, by using radiotracers that detect relevant biological reactions. A major impediment to expanding PET applications to study the brain has been the lack of radiotracers that can identify and measure specific types of neurons or glial cells. In this issue of the JCI, Van de Bittner and colleagues describe a promising step toward solving this problem by identifying and describing a radiotracer, [¹¹C]GV1-57, that appears to specifically label olfactory sensory neurons (OSNs), which are essential for olfaction (Figure 1). This tracer, if its specificity is confirmed, has the potential to become a prototype for future radiotracers that can identify other neuronal cell types and would allow visualization and in-depth characterization of these neurons and their genesis.

Authors

Helene Benveniste, Yuri Lazebnik, Nora D. Volkow

How does leptin restore euglycemia in insulin-deficient diabetes?

• Text
• PDF

Abstract

Insulin replacement is the cornerstone of type 1 diabetes (T1D) treatment; however, glycemic control remains a challenge. Leptin has been shown to effectively restore euglycemia in rodent models of T1D; however, the mechanism or mechanisms by which leptin exerts glycemic control are unclear. In this issue of the JCI, Perry and colleagues provide evidence that suppression of lipolysis is a key facet of leptin-mediated restoration of euglycemia. However, more work remains to be done to fully understand the antidiabetic mechanisms of leptin.

Authors

Douglas Oberlin, Christoph Buettner

Out of the frying pan: dietary saturated fat influences nonalcoholic fatty liver disease

• Text
• PDF

Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by excess accumulation of fat in the liver. In some cases, NAFLD is also accompanied by insulin resistance, resulting in metabolic dysfunction. Dietary fat content probably influences both NAFLD and insulin resistance; however, the immediate effects of fat consumption have not been fully explored. In this issue of the JCI, Hernández et al. evaluated hepatic glucose and lipid metabolism in humans and mice following a single oral dose of saturated fat. This one bolus of fat resulted in a measurable increase in insulin resistance, hepatic triglycerides, and gluconeogenesis. In mice, the saturated fat bolus resulted in the induction of several NAFLD-associated genes. Together, the results of this study indicate that saturated fat intake has immediate effects on metabolic function.

Authors

Elizabeth Parks, Hannele Yki-Järvinen, Meredith Hawkins

β Cells led astray by transcription factors and the company they keep

• Text
• PDF

Abstract

Pancreatic β cells have one of the highest protein secretion burdens in the body, as these cells must synthesize and secrete insulin in proportion to postprandial rises in blood glucose. Remarkably, it is now becoming clear that adult β cells retain plasticity and can dedifferentiate into embryonic fates or adopt alternate islet endocrine cell identities. This property is especially important, because changes in cell fate alter β cell function and could form the basis for defects in insulin secretion that occur early in the pathogenesis of the most prevalent form of β cell dysfunction, type 2 diabetes. In this issue, three different studies provide complementary perspectives on how the transcription factors NK2 homeobox 2 (NKX2.2), paired box 6 (PAX6), and LIM domain–binding protein 1 (LDB1) serve to maintain mature adult β cell identity, revealing clues as to how adult β cells can partially dedifferentiate or become reprogrammed into other islet endocrine cells.

Authors

Peter Thompson, Anil Bhushan