JCI online early table of contents: April 1, 2008

Although the drug IFN-beta is commonly used to treat individuals with the relapsing-remitting form of multiple sclerosis (MS), little is known about the mechanism(s) by which it acts. However, Genhong Cheng and colleagues, at the University of California at Los Angeles, have now reported a mechanistic pathway by which it reduces disease in a mouse model of MS known as EAE.

In addition to being a drug, IFN-beta is produced naturally by the body during certain immune responses. In the study, mice lacking a component of the molecule to which IFN-beta binds to mediate its effects were found to develop more severe EAE than mice expressing this protein. This was associated with increased numbers of immune cells known as Th17 cells in the central nervous system of the mice, the part of the body affected in individuals with MS. Further experiments showed that disease could be alleviated in these mice by administration of a soluble molecule known as IL-27, leading the authors to suggest that in individuals with MS, the beneficial effects of IFN-beta are likely to be mediated, at least in part, through its ability to induce the secretion of IL-27.

TITLE: The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice

AUTHOR CONTACT:
Genhong Cheng
University of California at Los Angeles, Los Angeles, California, USA.
Phone: (310) 825-8896; Fax: (310) 206-5553. Email: genhongc@microbio.ucla.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33342

Sickle cell disease (SCD) is so called because of the abnormal sickle shape of the red blood cells in individuals with this blood disorder. The abnormal shape of the red blood cells prevents them passing easily through blood vessels, which can become obstructed such that blood flow to an organ is restricted, causing pain and organ damage. An episode of blood vessel obstruction is known as a vaso-occlusive crisis (VOC) and a new study, performed by Pierre-Louis Tharaux and colleagues, at INSERM U689, France, has indicated that a drug known as bosentan prevents experimentally induced VOC in a mouse model of SCD.

In vivo analysis indicated that during experimentally induced VOC, blood vessel resistance was increased through a process mediated by the protein endothelin. As bosentan, which is used to treat individuals with pulmonary arterial hypertension, is a drug that acts as an antagonist of both endothelin receptors, the authors assessed its ability to treat experimentally induced VOC in a mouse model of SCD. The drug was found to have many beneficial effects that cumulated to prevent the death of the mice, leading to the suggestion that bosentan might provide a new way to limit VOC, and thereby organ damage, in individuals with SCD.

TITLE: Endothelin receptor antagonism prevents hypoxia-induced mortality and morbitity in a mouse model of sickle-cell disease

AUTHOR CONTACT:
Pierre-Louis Tharaux
INSERM U689, Paris, France.
Phone: 33-615-95-53-67; Fax: 33-14-81-31-28; E-mail: tharaux@chusa.jussieu.fr.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33308

How much we want to eat, in other words our appetite, and how much energy we burn, are both controlled by a hormone known as leptin. Leptin is made by fat tissue and it passes through the circulation to the brain, where it modifies the activity of several types of nerve cell, including POMC nerves, to signal to the body that it does not need to eat more and that it needs to burn more energy. As obesity can be caused if leptin-mediated signaling goes awry, much effort is being expended trying to identify the signaling pathways activated by leptin. Joel Elmquist and colleagues, at the University of Texas Southwestern Medical Center, Dallas, have provided new insight into the signaling pathways by which leptin mediates its effects on POMC nerves in mice.

In the study, analysis of the brain tissue of normal mice indicated that leptin caused rapid activation of POMC nerves. These effects of leptin could be blocked by inhibitors of a signaling molecule known as PI3K and mice with genetically disrupted PI3K signaling in POMC cells failed to activate the nerve cells in response to leptin. Furthermore, targeted disruption of PI3K interfered with leptin-induced suppression of feeding. Despite these short-term consequences, the absence of POMC PI3K signaling had no detectable impact on long-term regulation of body weight, leading the authors to propose that POMC PI3K signaling is essential for suppressing appetite, but that PI3K signaling in POMC neurons is not the primary signaling pathway by which leptin regulates long-term energy expenditure.

TITLE: Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mce

AUTHOR CONTACT:
Joel K. Elmquist
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-2911 Fax: (214) 648-5612; E-mail: joel.elmquist@utsouthwestern.edu.

MEDIA CONTACT:
Kristen Holland Shear
Office of News and Publications
The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-3404; E-mail: kristen.hollandshear@UTSouthwestern.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32964

Osteoclasts and osteoblasts are cells that have important but opposing roles in the maintenance of bone density — osteoclasts mediate bone destruction, whereas osteoblasts mediate bone formation. The generation of these cells types is tightly regulated and when disturbed it can lead to bone diseases such as osteoporosis. New data, generated by Shao-Cong Sun and colleagues, at The University of Texas MD Anderson Cancer Center, Houston, have now identified a role for the protein CYLD in regulating the generation of osteoclasts (a process also known as osteoclastogenesis) in mice.

In the study, osteoclastogenesis was found to be dysregulated in mice lacking the protein CYLD and this was associated with severe osteoporosis. Further analysis revealed the mechanism behind these defects — precursors of osteoclasts isolated from CYLD-deficient mice were hyperresponsive to RANKL-induced development leading to the production of more and larger osteoclasts. The authors therefore concluded that CYLD negatively regulates osteoclast generation induced by the protein RANKL and that the gene containing the information required to make the CYLD protein might be a genetic factor involved in the development of inherited bone disorders.

TITLE: Deubiquitinating enzyme CYLD regulates RANK signaling and osteoclastogenesis in mice

AUTHOR CONTACT:
Shao-Cong Sun
The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Phone: (713) 563-3218; Fax: (713) 563-3280; E-mail: ssun@mdanderson.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34257

Dystrophic epidermolysis bullosa (DEB) is a disorder characterized by fragile skin and associated with trauma-induced blistering, progressive soft tissue scarring, and an increased risk of developing skin cancer. It is a genetic disorder caused by mutations in the gene containing the information for making the protein collagen VII. In a new study, Leena Bruckner-Tuderman and colleagues, at the University Medical Center Freiburg, Germany, have developed a mouse model of DEB that characterizes the human disease very well, leading them to suggest that analysis of these mice might help researchers develop new and effective approaches to treating individuals with DEB.

Mice were engineered to express only low levels of collagen VII, about 10% of normal levels, and were found to develop the characteristic symptoms of DEB, including repeated skin blistering that led to tissue scarring (also known as fibrosis), which was caused by cells known as myofibroblasts. When normal fibroblast cells (which can give rise to myofibroblasts) were injected into the skin of the mutant mice, the treated area of skin was resistant to trauma-induced damage. By contrast, untreated areas of skin in the same mice remained susceptible to trauma-induced damage. These data led the authors to suggest that fibroblast-based treatments might provide a new avenue for the development of therapeutic strategies for DEB.

TITLE: A hypomorphic mouse model of dystrophic epidermolysis bullosa reveals mechanisms of disease and response to fibroblast therapy

AUTHOR CONTACT:
Leena Bruckner-Tuderman
University Medical Center Freiburg, Freiburg, Germany.
Phone: 49-671-270-6716; Fax: 49-671-270-6936; E-mail: bruckner-tuderman@uniklinik-freiburg.de.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34292

New data, generated in mice, by Guido Franzoso and colleagues at the University of Chicago, have provided insight into the molecular mechanisms underlying liver regeneration.

In the study, mice lacking the protein Gadd45-beta were found to exhibit decreased liver regeneration after part of their liver was removed, and this was due to decreased proliferation of liver cells and increased programmed cell death. These effects were associated with increased activity of the signaling molecule JNK, and the regenerative capacity of the liver was restored to normal if mice were engineered to lack JNK in addition to Gadd45-beta. Together, these data led the authors to suggest that suppressing the signaling molecule JNK might be beneficial during liver regeneration.

TITLE: Gadd45-beta promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling

AUTHOR CONTACT:
Guido Franzoso
University of Chicago, Chicago, Illinois, USA.
Phone: (773) 702-4729; Fax: (773) 702-3701; E-mail: gfranzos@midway.uchicago.edu. or g.franzoso@imperial.ac.uk.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33913

A crucial step in the formation of a blood clot (also known as a thrombus) is the adhesion of blood cells known as platelets to blood vessel walls. This step is mediated in part by interactions between the protein collagen in blood vessel walls and a protein complex on the surface of platelets comprised of GPVI and FcR-gamma. Although drugs targeting platelets benefit patients with various diseases caused by inappropriate blood clotting, such as heart disease, the safety and efficacy of current treatments are limited. A potential new treatment for such diseases has been suggested by the work of Hiroshi Takayama and colleagues, at The University of Shiga Prefecture, Japan.

It was shown that a mouse antibody that depletes GPVI from the surface of platelets can inhibit collagen-induced human platelet aggregation in vitro. This antibody also led to loss of GPVI on the surface of platelets when it was injected into monkeys. The mechanisms underlying this loss of GPVI were then shown to be cAMP-dependent endocytosis of antibody-bound GPVI. The authors therefore concluded that this approach might provide a new antiplatelet strategy for preventing diseases associated with inappropriate blood clotting.

TITLE: A novel antiplatelet antibody therapy that induces cAMP-dependent endocytosis of the GPVI/Fc receptor gamma-chain complex

AUTHOR CONTACT:
Hiroshi Takayama
The University of Shiga Prefecture, Shiga, Japan.
Phone: 81-749-28-8441; Fax: 81-749-28-8519; E-mail: htakayam@shc.usp.ac.jp.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32513

Pulmonary arterial hypertension (PAH) is an increase in blood pressure in one or more of the blood vessels supplying the lungs. It can lead to shortness of breath, dizziness, fainting, and, in severe cases, heart failure. A marked proportion of cases are associated with loss-of-function or decreased expression in the lungs of the protein BMP-RII. New data, generated using mice and cultured human cells, by Marlene Rabinovitch and colleagues at Stanford University School of Medicine, have identified a signaling axis downstream of BMP-RII that might help explain the association between PAH and loss-of-function or decreased expression of the protein BMP-RII.

In the study, BMP-2–induced BMP-RII signaling was shown to inhibit the growth of human and mouse smooth muscle cells by inducing the protein PPAR-gamma to bind DNA, and both BMP-2 and a PPAR-gamma agonist were found to induce smooth muscle cells to secrete a protein known as apoE. Further analysis of human and mouse smooth muscle cells expressing reduced amounts of BMP-RII and smooth muscle cells from mice lacking either PPAR-gamma or apoE clearly indicated that the antiproliferative effect of BMP-2 was dependent on BMP-RII, PPAR-gamma, and apoE. As mice lacking PPAR-gamma in their smooth muscle cells were observed to develop PAH, the authors have suggested that PPAR-gamma agonists might benefit individuals with PAH.

TITLE: An antiproliferative BMP-2/PPAR-gamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension

AUTHOR CONTACT:
Marlene Rabinovitch
Stanford University School of Medicine, Stanford, California, USA.
Phone: (650) 723-8239; Fax: (650) 723-6700; E-mail: marlener@stanford.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32503