EDITOR'S PICK: Estrens might not be the answer for osteoporosis
A new study appearing in the September issue of the Journal of Clinical Investigation indicates that caution might be needed if a new group of drugs known as estrens are to be developed for the treatment of osteoporosis. The researchers found that although estrens improved bone strength in mice with osteoporosis, they also had adverse effects on reproductive organs and human breast cancer cells.
Many individuals, in particular women who have gone through the menopause, suffer from osteoporosis -- a disease in which the bones become fragile and highly susceptible to fracture. Bone strength is naturally maintained by a group of hormones known as sex hormones (for example, estrogen). However, unnaturally high levels of these hormones cause cancer of the reproductive organs and breast tissue, meaning that they cannot be used to treat individuals with osteoporosis. So, researchers have long been searching for estrogen-like molecules that increase bone strength but do not cause cancer. Recently, a new set of molecules (known as estrens) said to have these properties were identified. However, the wisdom behind developing estrens for use in the clinic is questioned by Roland Baron and colleagues from Yale University. They showed that although mice with osteoporosis treated with estrens showed some improvement in bone strength, their reproductive organs increased in size. Furthermore, estrens induced the proliferation of human breast cancer cells. This study indicates that estrens might not be the sought after estrogen-like molecules that improve bone strength but do not cause cancer, and has important implications for their clinical development.
In an accompanying commentary, Ushma S. Neill from The Journal of Clinical Investigation discusses the evidence for and against the use of estrens to treat osteoporosis, and concludes that we will have to wait for the completion of clinical trials before we have a definitive answer.
TITLE: Bone protection by estrens occurs through non–tissue-selective activation of the androgen receptor
AUTHOR CONTACT:
Roland Baron
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: 203-785-4150; Fax: 203785-2744
E-mail: roland.baron@yale.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28809
ACCOMPANYING COMMENTARY
TITLE: You say estren, I say estrogen. Let's call the whole replacement off!
AUTHOR CONTACT:
Ushma S. Neill
The Journal of Clinical Investigation, New York, New York, USA.
Phone: 212-342-0497; Fax: 212-342-0499
E-mail: editors@the-jci.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29733
EDITOR'S PICK: Is liver damage down the TRAIL for a promising cancer therapy?
TRAIL is a protein that is considered a promising cancer therapeutic because it can kill tumor cells and can synergize with conventional chemotherapeutic agents to destroy tumor cells. However, controversy surrounds whether or not TRAIL affects nontumor cells, in particular cells of the liver -- which are known as hepatocytes. Now, Thomas Brunner and colleagues from the University of Bern in Switzerland show that although TRAIL alone does not kill mouse hepatocytes in vitro, it does enhance both in vitro and in vivo hepatocyte cell death induced by signaling through another protein on the surface of hepatocytes known as Fas. This study, which is published in the September issue of the Journal of Clinical Investigation, indicates that TRAIL can enhance hepatocyte cell death, and therefore liver damage, initiated by signaling through Fas. This has important clinical implications because cells that are able to trigger signaling through Fas are present in the liver, especially during inflammation, making liver damage a potential risk of TRAIL-based therapeutics.
TITLE: TRAIL receptor–mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and lethality
AUTHOR CONTACT:
Thomas Brunner
University of Bern, Bern, Switzerland.
Phone: 41-31-632-49-71; Fax: 41-31-381-87-64 E-mail: thomas.brunner@pathology.unibe.ch.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27726
CARDIOVASCULAR BIOLOGY: BAY 58-2667 spots the difference between diseased and normal blood vessels
Coronary heart disease and the many disorders that increase the risk of coronary heart disease (such as diabetes and high blood pressure) are associated with decreased blood flow to the muscles of the heart. One reason for this decreased blood flow is that blood vessels no longer respond to nitric oxide (NO), which binds a protein known as soluble guanylyl cyclase (sGC), triggering blood vessels to dilate. Drugs that are converted to NO in the body (and are therefore known as NO donors) have been used for many years to treat cardiovascular disease, but their effectiveness often rapidly decreases.
Now, Harald Schmidt and colleagues from Monash University, Australia, show in several animal models of cardiovascular disease and in human blood vessels from individuals with diabetes that a new drug (BAY 58-2667) can overcome one of the obstacles that leads to NO-donor ineffectiveness. In this study, which appears in the September issue of the Journal of Clinical Investigation, it is shown that the form of sGC found in diseased blood vessels differs from the sGC found in normal blood vessels and does not respond to NO. By contrast, activated sGC found in diseased blood vessels, but not sGC found in normal blood vessels, responded to BAY 58-2667 and triggered blood vessel dilation. This study might lead to the development of drugs that cause dilation of diseased blood vessels but not healthy ones.
In an accompanying commentary, Mark Gladwin discusses how this study raises many questions regarding the chemistry and mechanisms of NO-induced dilation of blood vessels.
TITLE: Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels
AUTHOR CONTACT:
Harald H. H. W. Schmidt
Monash University, Melbourne, Victoria, Australia.
Phone: 61-3-9905-5752; Fax: 61-3-9905-5729
E-mail: Harald.Schmidt@med.monash.edu.au.
Peter M. Schmidt
Monash University, Melbourne, Victoria, Australia.
Phone: 61-3-9902-0218; Fax: 61-3-9905-5851
E-mail: Peter.Schmidt@med.monash.edu.au.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28371
ACCOMPANYING COMMENTARY
TITLE: Deconstructing endothelial dysfunction: soluble guanylyl cyclase oxidation and the NO resistance syndrome
AUTHOR CONTACT:
Mark T. Gladwin
National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301-435-2310; Fax: 301-451-7091
E-mail: mgladwin@nih.gov.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29807
IMMUNOLOGY: A new source of regulatory T cells for humans
In humans, CD4+CD25hiFOXP3+ regulatory T cells (Tregs) function to prevent other T cells from destroying self-tissues. Understanding how they are generated is important for developing them for use in the clinic to stop the unwanted immune responses that occur in individuals with autoimmunity and in individuals who reject a transplant. The thymus (which is where T cell precursors develop into fully fledged T cells) was the only identified source of Tregs in humans and it shrinks in size at puberty. So, one potential mechanism postulated to allow the Treg population to be maintained as an individual ages was that Tregs are long-lived, self-regenerating cells. But researchers at the Windeyer Institute in London have now shown that this is highly unlikely to be true because while the proportion of functional Tregs does not decrease with age, human CD4+CD25hiFOXP3+ cells divide rapidly in vivo and are highly susceptible to a form of cell death known as apoptosis. This study appears in the September issue of the Journal of Clinical Investigation.
Arne Akbar and colleagues further showed that human Tregs seem to be derived outside the thymus from antigen-stimulated memory CD4+CD25-FOXP3- T cells. This study has important implications for researchers attempting to expand Tregs in vivo for therapeutic purposes, as well as for the treatment of individuals with chronic infections, who it seems, are likely to harbor many infection-specific Tregs that might suppress their immune system.
In an accompanying commentary, Lucienne Chatenoud and Jean-François Bach from Hôpital Necker-Enfants Malades in France discuss how these data seem to provide the first evidence of a population of adaptive Tregs (that is, Tregs generated following antigen stimulation in the periphery and not during development in the thymus) in humans that is similar to the population of adaptive Tregs found in mice.
TITLE: Human CD4+CD25hiFoxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo
AUTHOR CONTACT:
Arne N. Akbar
Windeyer Institute, London, United Kingdom.
Phone: 44-20-76799214; Fax: 44-20-76799545 E-mail: a.akbar@ucl.ac.uk.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28941
ACCOMPANYING COMMENTARY
TITLE: Adaptive human regulatory T cells: myth or reality?
AUTHOR CONTACT:
Jean-François Bach
Hôpital Necker-Enfants Malades, Paris, France.
Phone: 33-144-49-53-73; Fax: 33-143-06-23-88 E-mail bach@necker.fr.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29748
AUTOIMMUNITY: A beautiful new model for MS
Multiple sclerosis (MS) is a disease that affects the cells of the brain and spinal cord. MS can cause various symptoms, including depression, pain, and impaired mobility. Although it is clear that MS is caused by cells of the immune system inappropriately attacking the cells of the brain and spinal cord, much remains unknown about the disease. For example, what triggers the immune cells to attack; what is the identity of the attacking cell(s); and what determines which part of the brain is attacked? Answering these questions has been hampered by the lack of a suitable animal model of MS.
Now, a good, new mouse model of a form of MS -- known both as neuromyelitis optica (NMO) and Devic disease -- that only affects eyesight, limb movement, and bladder and bowel control is described in two independent papers to be published in the September issue of the Journal of Clinical Investigation. Analysis of these mice indicated that disease was caused by cooperation between two types of immune cell known as B cells and T cells. The independent development of this mouse model of NMO by Andreas Holz and colleagues from the Max Planck Institute for Neurobiology in Germany and Vijay Kuchroo and colleagues from Brigham and Women's Hospital in Boston should enable researchers to get more of a handle on the causes of both NMO and MS, thereby providing new avenues of research for the design of therapeutics to treat these debilitating diseases.
In an accompanying commentary, Richard Ransohoff from the Cleveland Clinic, Ohio, discusses why he believes that the mouse model of NMO developed by these two groups will in fact yield more insight into the mechanisms of MS than the mechanisms of NMO.
TITLE: Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation
AUTHOR CONTACT:
Andreas Holz
Max Planck Institute for Neurobiology, Martinsried, Germany.
Phone: 49-89-8578-3561; Fax: 49-89-8995-0170
E-mail: holz@neuro.mpg.de.
Hartmut Wekerle
Max Planck Institute for Neurobiology, Martinsried, Germany.
Phone: 49-89-8578-3551; Fax: 49-89-8578-3790
E-mail: hwekerle@neuro.mpg.de.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28330
RELATED MANUSCRIPT
TITLE: Myelin oligodendrocyte glycoprotein–specific T and B cells cooperate to induce a Devic-like disease in mice
AUTHOR CONTACT:
Vijay K. Kuchroo
Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617-525-5350; Fax: 617-525-5566 E-mail: vkuchroo@rics.bwh.harvard.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28334
ACCOMPANYING COMMENTARY
TITLE: A mighty mouse: building a better model of multiple sclerosis
AUTHOR CONTACT:
Richard M. Ransohoff
Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Phone: 216-444-0627; Fax: 216-444-7927 Email: ransohr@ccf.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29834
AUTOIMMUNITY: Virus pulls the trigger for autoimmunity
Autoimmune diseases are caused by cells of the immune system (in particular, B cells and T cells) attacking and destroying other cells in the body. Although it is not clear exactly what triggers the immune cells to attack, there is some evidence that viral infection can instigate the destruction. In a study appearing in the September issue of the Journal of Clinical Investigation, Karl Lang and colleagues in Switzerland have now shown that signals through a protein known as Toll-like receptor 3 (TLR3), which could be provided by viral infection, are required to cause disease in a mouse model of autoimmune hepatitis.
The authors showed that mice with T cells that could recognize the cells of the liver did not attack the liver unless instructed to do so by other immune cells in the liver. Importantly, these other immune cells did not issue the order to attack unless they were stimulated through TLR3. Because the immune system recognizes some viruses through TLR3, this study improves our understanding of what could trigger autoimmune disease. However, as Marco Colonna from Washington University states in an accompanying commentary "…a full understanding of the role of viruses in human autoimmune diseases awaits the identification of…[all the molecules that can sense viruses]…and the viruses responsible for triggering them."
TITLE: Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling
AUTHOR CONTACT:
Karl S. Lang
University Hospital, Zurich, Switzerland.
Phone 41-1-255-2734; Fax: 41-1-255-4420
E-mail: karl.lang@usz.ch.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28349
ACCOMPANYING COMMENTARY
TITLE: Toll-like receptors and IFN-alpha: partners in autoimmunity
AUTHOR CONTACT:
Marco Colonna
Washington University School of Medicine, St Louis, Missouri, USA.
Phone: 314-362-0367; Fax: 314-362-4096
Email: mcolonna@pathology.wustl.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29879
VASCULAR BIOLOGY: The endothelial-cell wall: built by FoxM1
Devastating consequences can arise if the cells that form the barrier between the blood and the tissues are damaged, because cells and fluid from the blood can enter the tissues unhindered. For example, in the lung, damage to these barrier cells (known as endothelial cells) can cause acute respiratory distress syndrome -- which is what individuals infected with the SARS virus eventually succumb to -- and acute lung injury (ALI). However, the severity of the problem that arises depends in part on how quickly the endothelial cells are able to recover and reform the barrier. Little was known about what controls the reformation of this barrier.
Now, in a study appearing in the September issue of the Journal of Clinical Investigation, Asrar Malik and colleagues from the University of Illinois in Chicago have shown that mice lacking a protein known as forkhead box M1 (FoxM1) were significantly impaired in their ability to reform the endothelial-cell barrier in the lung after it had been damaged. Substantially more cells and fluid from the blood were able to enter the lungs of these mice compared with normal mice, and this meant that they had an increased risk of death. The authors therefore suggest that boosting the function of FoxM1 might be beneficial to patients whose lung endothelial-cell barrier has been damaged. In an accompanying commentary, Issei Komuro concurs, stating that "Although considerable work will be required, promotion of endothelial regeneration would be a novel approach to treat ALI".
TITLE: Endothelial cell–restricted disruption of FoxM1 impairs endothelial repair following LPS-induced vascular injury
AUTHOR CONTACT:
Asrar B. Malik
University of Illinois College of Medicine, Chicago, Illinois, USA.
Phone: 312-996-7635; Fax: 312-996-1225
E-mail: abmalik@uic.edu.
You-Yang Zhao
University of Illinois College of Medicine, Chicago, Illinois, USA.
Phone: 312-355-0238; Fax: 312-996-1225
E-mail: yyzhao@uic.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27154
ACCOMPANYING COMMENTARY
TITLE: Regeneration of the endothelium as a novel therapeutic strategy for acute lung injury
AUTHOR CONTACT:
Issei Komuro
Chiba University Graduate School of Medicine, Chiba, Japan.
Phone: 81-43-226-2097; Fax: 81-43-226-2557
E-mail: komuro-tky@umin.ac.jp.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29637
DEVELOPMENT: Cholesterol precursors can cause developmental defects
Although high levels of cholesterol are bad for us (putting us at increased risk of a heart attack), low levels of cholesterol can also be bad -- as a fetus, low levels of cholesterol are associated with life-long disabilities, such as learning difficulties, limb abnormalities, and cleft palate. Low levels of cholesterol during development are caused by genetic defects in the proteins that control the production of cholesterol. Therefore, these individuals not only have low levels of cholesterol but also high levels of cholesterol precursors; which of these cause the developmental defects has been a matter of debate. Now, researchers from the University of Texas Southwestern Medical Center have shown that in mice it is the high levels of cholesterol precursors that are to blame.
In their study, which appears in the September issue of the Journal of Clinical Investigation, Joseph Goldstein and colleagues found that fetal mice with normal levels of cholesterol but very high levels of cholesterol precursors had severe developmental defects, including cleft palate. Treating female mice during pregnancy with a statin (a drug that decreases the production of cholesterol) reduced the level of cholesterol precursors in the fetal mice and decreased the incidence of cleft palate. This study provides enormous insight into why certain gene defects cause disability.
In an accompanying commentary, Forbes Porter from the National Institutes of Health puts this work in context with other recent advances and outlines the work that remains before we can fully understand how high levels of cholesterol precursors cause disabilities.
TITLE: Severe facial clefting in Insig-deficient mouse embryos caused by sterol accumulation and reversed by lovaststin
AUTHOR CONTACT:
Joseph L. Goldstein
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: 214-648-2141; Fax: 214-648-8804
E-mail: joe.goldstein@utsouthwestern.edu.
Michael S. Brown
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: 214-648-2179; Fax: 214-648-8804
E-mail: mike.brown@utsouthwestern.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28988
ACCOMPANYING COMMENTARY
TITLE: Cholesterol precursors and facial clefting
AUTHOR CONTACT:
Forbes D. Porter
National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301-435-4432; Fax: 301-480-5791;
E-mail: fdporter@mail.nih.gov.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29872
PARASITOLOGY: T. gondii can't hide from CD40
Toxoplasma gondii is a parasite that is a major problem for individuals whose immune system is compromised, such as transplant recipients and individuals infected with HIV, but it is controlled easily by healthy individuals. Now, researchers from the University of Cincinnati who studied both mouse and human cells in vitro have identified a potential reason for this difference: the immune system of healthy individuals is able to prevent T. gondii from hiding and escaping destruction.
Macrophages are an important immune cell type that can take up pathogens and destroy them. However, some pathogens, including T. gondii, are able to survive inside macrophages because they hide from the destruction machinery of the cell. In a study appearing in the September issue of the Journal of Clinical Investigation, Carlos Subauste and colleagues found that triggering macrophages through a protein on their surface known as CD40 initiated the destruction of T. gondii. In fact, T. gondii in macrophages triggered through CD40 were routed for destruction along a pathway known as the autophagy pathway. Because CD40L, which is the binding partner for CD40, is expressed by other cells of the immune system, this study provides a potential explanation for why only healthy individuals, and not individuals whose immune system is compromised, are able to control infection with T. gondii: CD40L-expressing cells are only available to trigger macrophage destruction of T. gondii in healthy individuals.
TITLE: CD40 induces macrophage anti–Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes
AUTHOR CONTACT:
Carlos S. Subauste
Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Phone: 216-844-8590; Fax: 216-844-7117
E-mail: carlos.subauste@case.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28796
Journal
Journal of Clinical Investigation