JCI table of contents: September 14, 2006

EDITOR'S PICK: Can Gleevec help patients with rheumatoid arthritis?

Imatinib mesylate (Gleevec; Novartis) is often the treatment of choice for individuals with either chronic myelogenous leukemia or gastrointestinal stromal tumors. Now, in a study appearing online on September 14 in advance of publication in the October print issue of the Journal of Clinical Investigation, researchers from Stanford University have shown that imatinib can block the development of disease in a mouse model of rheumatoid arthritis (RA), providing hope of a new treatment for RA.

Although there are two documented cases in which individuals taking imatinib to treat their cancer showed clinical improvement in their RA, there had been no study of the effects of imatinib in a mouse pre-clinical model of RA. So, William Robinson and colleagues administered imatinib to mice with an RA-like disease. Imatinib both prevented the onset of disease and the development of established disease. It did this by inhibiting the function of many of the immune cells that contribute to disease in patients with RA. Importantly, imatinib was also shown to inhibit the proliferation of cells taken from the joints of patients with RA. This study indicates that imatinib might provide relief to the many individuals suffering from RA.

TITLE: Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis

AUTHOR CONTACT:
William H. Robinson University of Stanford Medical School, Palo Alto, California, USA. Phone : (650) 849-1207 Fax: (650) 849-1208; E-mail: wrobins@stanford.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28546


EDITOR'S PICK: AM: A gene that affects female fertility

Complications in pregnancy can arise because of both fetal deficiencies and maternal deficiencies. Previous studies in the Caron laboratory have shown that mouse embryos lacking both copies of the gene encoding a protein known as adrenomedullin (AM) die at embryonic day 14.5 (E14.5). But now, Kathleen Caron and colleagues at the University of North Carolina at Chapel Hill show that female mice expressing reduced levels of the gene encoding AM have severely decreased fertility. It is therefore possible that modest alterations in human expression of the gene encoding AM might have implications for fertility.

In the study, which appears online on September 14 in advance of publication in the October print issue of the Journal of Clinical Investigation, it was shown that female mice with only one copy of the gene encoding AM (AM+/- mice) crossed with wild-type male mice have smaller litters than wild-type female mice crossed with either AM+/- or wild-type male mice. Reduced litter size was associated with fetal-growth restriction and embryo loss at E9.5–E12.5, which is when the placenta develops. Indeed, the placentas of growth-restricted embryos were closely spaced and showed morphologic and histologic defects. This study shows that in female mice a reduction in the level of AM severely decreases their fertility by affecting implantation and placental development, and suggests that in humans a small decrease in AM expression could negatively impact a woman's fertility.

TITLE: Reduced maternal expression of adrenomedullin disrupts fertility, placentation, and fetal growth in mice

AUTHOR CONTACT:
Kathleen M. Caron The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Phone: (919) 966-5215; Fax: (919) 966-5230; E-mail: Kathleen_caron@med.unc.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28462


METABOLIC DISEASE: TNF-alpha makes obese rodents put on weight

Although we know that an individual becomes obese when the number of calories they consume is greater than the number burned by their body, much remains to be learned about what controls the number of calories the body burns. In a study appearing online on September 14, in advance of publication in the October print issue of the Journal of Clinical Investigation, researchers from the University of Milan, Italy, show that the soluble proinflammatory factor TNF-alpha decreases the amount of energy burned by a cell and increases the amount of weight gained by obese rodents.

Enzo Nisoli and colleagues showed that the number and energy burning function of mitochondria, the compartments in a cell where calories are burned to provide the cell with energy, in muscle cells and fat cells was decreased in three different rodent models of obesity. If the rodents lacked one of the receptors for TNF-alpha, the number and energy burning function of the mitochondria in the muscle and fat cells increased and, most importantly, the animals gained less weight. Conversely, the number and energy burning function of mitochondria in muscle and fat cells decreased after in vitro treatment with TNF-alpha. Because obesity is associated with chronic inflammation, this study provides insight into a molecular pathway that might sustain obesity.

TITLE: TNF-alpha downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents

AUTHOR CONTACT:
Enzo Nisoli University of Milan, Milan, Italy. Phone: +39-02-50319684; Fax: +39-02-50319682; E-mail: enzo.nisoli@unimi.it.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28570


ONCOLOGY: HoxA proteins a problem for acute myeloid leukemia

Acute myeloid leukemia (AML) is the most common form of acute leukemia to affect adults, and its incidence increases with age. It is characterized by a large number of abnormal myeloid-type immune cells in the blood. A proportion of patients with AML have a genetic defect in mixed-lineage leukemia (MLL). One of these genetic defects, which is associated with a very poor outcome, occurs when part of the MLL gene is duplicated. But how this genetic defect contributes to AML was unknown.

Now, in a study appearing online on September 14, in advance of publication in the October print issue of the Journal of Clinical Investigation, Michael Caligiuri and colleagues from Ohio State University, show that although mice with a duplication in their Mll gene do not develop cancer, they do have dramatically increased numbers of the normal precursors of myeloid-type immune cells. This was because members of the HoxA gene family that control the development of myeloid-type immune cells were inappropriately switched on. This study provides insight into how the MLL gene duplication event might contribute to AML, but further work will be needed to determine what else is required for these increased numbers of normal myeloid-type immune cell precursors to become cancerous.

TITLE: Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations

AUTHOR CONTACT:
Michael A. Caligiuri Ohio State University, Columbus, Ohio, USA. Phone: (614) 293-7521; Fax: (614) 293-7522; E-mail: michael.caligiuri@osumc.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=25546


NEUROBIOLOGY: Separating muscle damage from neurodegeneration in Kennedy disease

Kennedy disease is a neurodegenerative disorder caused by mutations in the gene encoding the receptor for testosterone, the androgen receptor (AR). Although it is characterized by muscle weakness caused by neurodegeneration, individuals with Kennedy disease often first suffer from muscle cramps. How the diseases progresses from muscle cramps to neuromuscular weakness is not clear. So, Andrew Lieberman and colleagues from the University of Michigan generated mice expressing the mutated form of human AR (AR113Q mice). In their study, which appears online on September 14 in advance of publication in the October print issue of the Journal of Clinical Investigation, male AR113Q mice were shown to have similar characteristics to individuals with Kennedy disease. Importantly, the muscles of male AR113Q mice became damaged before the neurodegenerative process began. One consequence of this early damage to the muscles was decreased expression of a number of soluble factors that support the survival of neurons. This study indicates that the initial damage to muscle cells might be one cause of the neurodegeneration that characterizes Kennedy disease. The authors therefore suggest that therapeutics targeting this initial muscle damage might provide benefit to individuals with Kennedy disease.

TITLE: Androgen-dependent pathology demonstrates myopathic contribution to the Kennedy disease phenotype in a mouse knock-in model

AUTHOR CONTACT:
Andrew P. Lieberman University of Michigan Medical School, Ann Arbor, Michigan, USA. Phone: (734) 936-1887 Fax: (734) 615-3441 E-mail: liebermn@umich.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28773

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Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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