JCI Table of Contents, 15 July 2004

07/11/04

SUMMARIES OF PAPERS IN THIS ISSUE
Stem Cells Get a Workout
Female Infertility camp
Getting to the HAART of Bone Loss
ApoA-IV has the Guts to Fight Inflammation
Not by Mutation Identification Alone

OTHER PAPERS IN THIS ISSUE
Fat Gets Cut Away from Insulin Resistance
Pulmonary Fibrosis Polarized by Cytokines
Anuerysms in Allografted aorta
IDO says Don't to Asthma
IDO Can Do Anergy
HCV Mutation Impairs T Cell Inductionb
Noncanonical Insulin Target Tissues in Diabetes

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Stem Cells Get a Workout

Muscular dystrophies are characterized by severe muscle damage, ultimately through the loss of the ability to regenerate muscle. Generating alternative sources for precursor cells to replenish muscle fibers offers a potential therapeutic strategy to treat myopathies. Yvan Torrente and colleagues, from the University of Milan, having previously shown that a cellular marker called AC133 is required for muscle precursor cells to differentiate into mature muscle, the researchers now demonstrate that AC133-positive stem cells are a promising new source for replenishing muscle satellite cells that are depleted in muscular dystrophies. The researchers isolated human AC133-positive stem cells from normal blood. After growth in culture, these cells were subsequently injected into the skeletal muscle tissue of mice that are a model for human Duchene muscular dystrophy. The human stem cells invaded the damaged muscle fibers, expressed muscle fiber markers, and formed functional myofibers that restored muscle function. The injected mice also experienced amelioration of the clinical symptoms of muscular dystrophy and a restoration of the satellite cell pool required for muscle regeneration. This study provides new leads in the treatment of these debilitating muscle diseases.

TITLE: Human circulating AC133+ stem cells restore dystrophin expression and ameliorate function in dystrophic skeletal muscle

AUTHOR CONTACT:
Yvan Torrente
University of Milan, Padiglione Ponti, Ospedale Policlinico, via Francesco Sforza 35, 20122 Milan, Italy.
Phone: 39-02-55033874; Fax: 39-02-50320430; E-mail: torrenteyvan@hotmail.com

View the PDF of this article at: https://www.the-jci.org/press/20325.pdf

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Female infertility cAMP

In mammals, the development of the egg in the ovary is halted until just before ovulation, at which point the final cellular division to form the egg, called meiosis, is completed. Researchers have shown that this final step in egg maturation can be blocked by a chemical called cyclic AMP (cAMP) in a test tube, but it remained uncertain whether the same molecular mechanism occurred in the animal. To investigate this process, Vincent Manganiello, Marco Conti, and colleagues, from the National Institutes of Health and Stanford University School of Medicine, created a mouse that is deficient in a protein whose function is to destroy cAMP in the developing egg. This protein is called cyclic nucleotide phosphodiesterase 3A or PDE3A. Male mice that are missing their PDE3A gene are healthy and completely fertile. Female mice without the PDE3A gene are likewise healthy and can carry out ovulation, but they are completely infertile. The researchers showed that in the developing eggs in the absence of any PDE breakdown of cAMP, cAMP levels were substantially higher and that the developing eggs were frozen at a stage just prior to the completion of meiosis. The researchers then showed that by blocking the activity of another protein in the cAMP molecular signaling pathway, egg maturation could be completed in a test tube. The apparently reversible nature of the infertility block caused by innactivation of the Pde3a gene suggests that PDE3A may be a potential target for developing new contraceptives. The Pde3a knockout mouse will be an excellent model of female infertility for exploring this further.

TITLE: Cyclic nucleotide phosphodiesterase 3A–deficient mice as a model of female infertility

AUTHOR CONTACTS:
Vincent Manganiello
NHLBI, NIH 9000 Rockville Pike, Bethesda, Maryland 20892, USA. Phone: NHLBI Communications Office 301-496-4236; Fax: 301-402-1610; E-mail: ManganiV@nhlbi.nih.gov

Marco Conti
Stanford University Medical Center, 300 Pasteur Dr. Stanford, CA 94305-5317, USA
Phone: 650-725-6802; Fax: 650-725-7102; E-mail: marco.conti@stanford.edu

View the PDF of this article at: https://www.the-jci.org/press/21804.pdf

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Getting to the HAART of Bone Loss

While bone loss is not a standard clinical condition in HIV patients, it can become one when an HIV patient goes on highly active antiretroviral therapy (HAART). One partt of HAART is the use of HIV protease inhibitors (PI), and it is these drugs that have been implicated in patient bone loss when undergoing this treatment. While one PI called indinavir has been shown to interfere with the function and development of bone synthesizing cells called osteoblasts, proof that this entire family of drugs is involved in bone loss has yet to be established. F. Patrick Ross and colleagues, from the Washington University School of Medicine, investigate another standard PI used in HAART called ritonavir, which surprisingly does not effect osteoblasts, but instead interferes with osteoclasts, the bone destroying cells. The work here provides a detailed examination of the molecular underpinnings involved in ritonavir's inhibition of bone resorption, showing that it works by inhibiting a key element in osteoclast development and function, the function of a receptor activator called RANKL. Ritonavir specifically inhibits the ability of RANKL to activate two cellular signaling pathways (one through a protein called NF-kB and the other through a protein called Akt) that are critical to the formation and function of osteoclasts. The work here indicates that ritonavir may a PI family member that is bone sparing and therefore able to prevent bone-loss in patients undergoing HAART, and the specific molecular mechanisms uncovered here may aid in understanding the side-effects unique to different protease inhibitors.

TITLE: The HIV protease inhibitor ritonavir blocks osteoclastogenesis and function by impairing RANKL-induced signaling

AUTHOR CONTACT:
F. Patrick Ross
Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Phone: 314-454-8079; Fax: 314-454-5505; E-mail: rossf@medicine.wustl.edu

View the PDF of this article at: https://www.the-jci.org/press/15797.pdf

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ApoA-IV Has the Guts to Fight Inflammation

A protein called apolipoprotein A-IV (apoA-IV) has been shown to protect mice from atherosclerosis. One explanation for this is that apoA-IV has anti-inflammatory properties. If this is the case, then apoA-IV should likewise be protective in other diseases resulting from inflammatory reactions, such as inflammatory bowel disease. Theodore Kalogeris and colleagues at Louisiana State University Health Sciences Center investigate such protective properties of apoA-IV in a mouse model for human ulcerative colitis. By feeding mice with a heparin-like polysaccharide called dextransulfate sodium (DSS), the authors induced colitis that has several characteristics of human ulcerative colitis. In experiments examining DSS-induced colitis in mice that were given exogenous apoA-IV and in mice missing their apoA-IV gene, the data all showed that apoA-IV provided profound protection from colitis development, and presented evidence that the inflammatory response to DSS was increased in the absence of apoA-IV. The work here provides the first direct support for apoA-IV being an endogenous anti-inflammatory protein and presents information on the molecular mechanisms underlying this activity.

TITLE: Apolipoprotein A-IV inhibits experimental colitis

AUTHOR CONTACT:
Theodore J. Kalogeris
Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA.
Phone: 318-675-4354; Fax: 318-675-6005; E-mail: tkalog@lsuhsc.edu

View the PDF of this article at: https://www.the-jci.org/press/21233.pdf

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Not by Mutation Identification Alone

The identification of a mutation causing a genetic disease is only the first step in understanding that disease. To begin to consider treatments for such disease, researchers need to understand how these genetic defects play a role in the molecular pathophysiology of the disease. A case in point is Marfan syndrome. Marfan syndrome is a dominant connective tissue disorder whose main characteristics are aortic aneurysm and dissection, ocular lens dislocation, and long bone overgrowth. In 1991, a mutation in a gene called fibrillin-1 was identified as the cause of the disease. At that time many felt that the molecular impact of this mutation in disease development could be explained by what is called a dominant negative mechanism, which is that the mutated fibrillin-1 proteins created by this single mutated gene would interfere with the normal mechanisms for building connective tissue. While this molecular explanation seemed to hold true for many of the disease characteristics, there were several that could not be explained by this mechanism. Now, Harry Dietz and colleagues from Johns Hopkins University School of Medicine, provide a series of experiments, utilizing mouse genetic models of the disease, that show a dominant negative mechanism does not underpin Marfan syndrome, but instead that the mechanism of haploinsufficiency, of simply having half of the normal amount of fibrillin-1 protein, is actually responsible for this disorder. The authors show that over-expressing a mutant form of the fibrillin-1 gene in mice does not, as would be expected in the dominant-negative model, reconstitute the disease phenotype. The researchers were, however, able to create a mouse with Marfan disease characteristics by creating a mouse with one fibrillin-1 gene mutated in a manner similar to that in human Marfan disease. They then showed that by introducing back the wild-type gene into a mouse with the mutant genetic background, they could prevent disease formation. All of these data show that it is not the presence of a mutated protein that causes the main disease traits of Marfan syndrome, but rather the absence of the usual amount of normal protein.

An accompanying commentary by Peter Byers, of the University of Washington, provides history on Marfan disease and detailed information on the structure and function of fibrillin-1 and how reduction of the normal amount of this protein effects normal TGFb signaling thus contributing to many of the previously unexplained traits of the disease.

TITLE: Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome

AUTHOR CONTACT:
Harry C. Dietz
Johns Hopkins University School of Medicine, 720 Rutland Ave., Baltimore, MD 21205, USA. Phone: 410-614-0701; Fax: 410-614-2256; E-mail: hdietz@jhmi.edu

View the PDF of this article at:https://www.the-jci.org/press/20641.pdf

ACCOMPANYING COMMENTARY: Determination of the molecular basis of Marfan syndrome: a growth industry

AUTHOR CONTACT:
Peter H. Byers
University of Washington, Seattle, WA 98195, USA.
Phone: 206-543-4206; Fax: 206-616-1899; E-mail: pbyers@u.washington.edu

View the PDF of this article at: https://www.the-jci.org/press/22399.pdf

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OTHER PAPERS IN THIS ISSUE

Fat Gets Cut Away from Insulin Resistance

TITLE: Hypertension and abnormal fat distribution but not insulin resistance in mice with P465L PPARg

AUTHOR CONTACT:
Nobuyo Maeda
University of North Carolina, Chapel Hill, NC 27599, USA.
Phone: 919-966-6914; Fax: 919-966-8800; E-mail: nobuyo@med.unc.edu

View the PDF of this article at: https://www.the-jci.org/press/20964.pdf

ACCOMPANYING COMMENTARY: Unbuckling lipodystrophy from insulin resistance and hypertension

AUTHOR CONTACT:
Robert A. Hegele
Robarts Research Institute, 406-100 Perth Drive, London, Ontario N6A 5K8, Canada.
Phone: 519-663-3461: Fax: 519-663-3037; E-mail: hegele@robarts.ca

View the PDF of this article at: https://www.the-jci.org/press/22382.pdf

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Pulmonary Fibrosis Polarized by Cytokines

TITLE: Regulation of pulmonary fibrosis by chemokine receptor CXCR3

AUTHOR CONTACT:
Paul W. Noble
Yale University School of Medicine, New Haven, CT 06520, USA.
Phone: 203-785-3627; Fax: 203-785-3826; E-mail:paul.noble@yale.edu

View the PDF of this article at: https://www.the-jci.org/press/16861.pdf

ACCOMPANYING COMMENTARY: Innate immunity dictates cytokine polarization relevant to the development of pulmonary fibrosis

AUTHOR CONTACT:
Robert M. Strieter
David Geffen School of Medicine, UCLA, 900 Veteran Avenue, Los Angeles, CA 90095, USA.
Phone: 310-794-1999; Fax: 310-794-1998; E-mail: rstrieter@mednet.ucla.edu

View the PDF of this article at: https://www.the-jci.org/press/22398.pdf

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Aneurysms in Allografted Aortas

TITLE: Th2-predominant inflammation and blockade of IFN-gamma signaling induce aneurysms in allografted aortas

AUTHOR CONTACT:
Koichi Shimizu
Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Phone: 617-525-4556; Fax: 617-525-4380; E-mail: ksmz@rics.bwh.harvard.edu

View the PDF of this article at: https://www.the-jci.org/press/19855.pdf

ACCOMPANYING COMMENTARY: Adaptive cellular immunity in aortic aneurysms: cause, consequence, or context?

AUTHOR CONTACT:
Robert W. Thompson
Washington University School of Medicine, One Barnes-Jewish Hospital Plaza, St. Louis, MO 63110, USA.
Phone: 314-362-7410; Fax: 314-747-3548; E-mail: thompsonr@msnotes.wustl.edu

View the PDF of this article at: https://www.the-jci.org/press/22309.pdf

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IDO Says Don't to Asthma

TITLE: Inhibition of experimental asthma by indoleamine 2,3-dioxygenase

AUTHOR CONTACT:
Eyal Raz,
University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Phone: 858-534-5444; Fax: 858-534-5399; E-mail: eraz@ucsd.edu

View the PDF of this article at: https://www.the-jci.org/press/21275.pdf

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IDO Can Do Anergy

TITLE: Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes

AUTHOR CONTACT:
David H. Munn
Medical College of Georgia, Augusta, Georgia 30912, USA.
Phone: 706-721-7141; Fax: 706-721-8732; E-mail: dmunn@mail.mcg.edu

View the PDF of this article at: https://www.the-jci.org/press/21583.pdf

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HCV Mutation Impairs T Cell Induction

TITLE: Hepatitis C virus mutation affects proteasomal epitope processing

AUTHOR CONTACT:
Barbara Rehermann
NIDDK, NIH, 10 Center Drive, Bethesda, MD 20892, USA.
Phone: 301-402-7144; Fax: 301-402-0491; E-mail: Rehermann@nih.gov

View the PDF of this article at: https://www.the-jci.org/press/20985.pdf

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Noncanonical Insulin Target Tissues in Diabetes

TITLE: Transgenic rescue of insulin receptor-deficient mice

AUTHOR CONTACT:
Domenico Accili
Columbia University, 1150 St. Nicholas Ave., New York, NY 10032, USA
Phone: 212-851-5332; Fax: 212-851-5331; E-mail: da230@columbia.edu

View the PDF of this article at: https://www.the-jci.org/press/21645.pdf

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