Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Top
  • View PDF
  • Download citation information
  • Send a comment
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal
  • Top
  • Atrophy impaired
  • Having the stomach for PAR1 activity
  • Hobbling free α-hemoglobin
  • Converging on scatter factor
  • Version history
  • Article usage
  • Citations to this article

Advertisement

In this issue Free access | 10.1172/JCI120011

In This Issue

Published November 15, 2004 - More info

Published in Volume 114, Issue 10 on November 15, 2004
J Clin Invest. 2004;114(10):1361–1361. https://doi.org/10.1172/JCI120011.
© 2004 The American Society for Clinical Investigation
Published November 15, 2004 - Version history
View PDF
Atrophy impaired

Extended bed rest, limb immobilization, and sedentary lifestyles all lead to muscle atrophy. However, the underlying molecular processes remain largely unknown. Recent evidence has implicated NF-κB, p50, and B cell lymphoma 3 (Bcl-3) proteins in the induction of atrophy in disused muscles. Susan Kandarian and R. Bridge Hunter extend these findings using mice deficient in p105/p50 (Nfkb1) and in Bcl3 (pages 1504–1511). They found that, unlike wild-type mice, Nfkb1-deficient mice subject to 10 days of hindlimb unloading do not show a decreased area in soleus fiber cross-section, and this observation was accompanied by loss of luciferase expression from an NF-κB reporter in the soleus. Experiments on the Bcl3-knockout mice yielded similar results. Fast fibers atrophied to a greater degree than slow fibers in wild-type mice, while fast fibers were primarily atrophy resistant in the Bcl3- and Nfkb1-deficient mice. In both the Bcl3–/– and Nfkb1–/– mice, the slow-to-fast shift in myosin isoform expression was eliminated. The results indicate that Bcl3 and Nfkb1 are required for atrophy to occur in disused muscles and for the transition of the associated phenotype. See figure

Having the stomach for PAR1 activity

Inflammatory bowel disease (IBD) is thought to result from a variety of genetic and environmental factors; however, a great deal more work is required to obtain a complete picture of the pathogenesis of IBD. Protein-activated receptor–1 (PAR1) is highly expressed in several types of gastrointestinal cells and is activated through cleavage by thrombin, an activity that is increased in the colon of patients with IBD. Nathalie Vergnolle and colleagues examined the impact of PAR1 activity in IBD (pages 1444–1456). They found that PAR1 is overexpressed in the colons of patients with IBD. In intracolonic tests in mice, PAR1 agonists caused an inflammatory response that included edema and infiltration by granulocytes. In SCID mice, PAR1-induced inflammation was shown to require T and B cell involvement. In different mouse models of IBD, PAR1 activation was shown to increase the severity and duration of intestinal inflammation, while PAR1 antagonism greatly reduced this severity and associated mortality. In both models, colitis was dramatically curtailed by PAR1 deficiency. This work points to the importance of PAR1 activity in the pathogenesis of IBD and indicates that inhibition of PAR1 may be useful in treating IBD and other chronic intestinal inflammatory conditions. See figure

Hobbling free α-hemoglobin

Hemoglobin (Hb) synthesis is carefully coordinated to avoid accumulation of free α- or β-Hb subunits, which can be cytotoxic. In the disease β-thalassemia, mutations that result in the loss of β-Hb leave α-Hb subunits unpaired. Precipitates of unpaired α-Hb produce damaging ROS that reduce the lifespan of circulating erythrocytes. In vitro studies have demonstrated that the α-Hb–stabilizing protein (AHSP) binds α-Hb and prevents its precipitation, indicating that it may function in vivo to limit damage caused by free α-Hb. Mitchell Weiss and colleagues investigated the in vivo importance of AHSP in limiting free α-Hb toxicity by developing an AHSP-deficient mouse (pages 1457–1466). These mice had short-lived erythrocytes that also contained Hb precipitates. Examination of hematopoietic tissues revealed higher numbers of erythrocyte precursors but also elevated levels of apoptosis. Biochemical analysis of AHSP–/– erythrocytes revealed evidence of oxidative damage and increased ROS as compared with wild-type erythrocytes. Additionally, purified recombinant AHSP inhibited α-Hb ROS production in vitro. Finally, mice that had β-thalassemia and were AHSP–/– had a more severe phenotype than did β-thalassemia mice. These data together indicate an essential role for AHSP during Hb production and erythropoiesis. This study also has suggests that developing the means to alter human AHSP expression could reduce the severity of β-thalassemia.

Converging on scatter factor

Scatter factor (SF) controls the proliferation, motility, survival, and morphology of a variety of tissues by promotion of a genetically programmed form of invasive growth in both physiological and pathological processes. SF is produced in a precursor form (pro-SF) that must be cleaved to activate its high-affinity receptor, the Met tyrosine kinase. Paolo Michieli and colleagues developed an uncleavable form of SF and used it in a gene-therapy approach to inhibit invasive tumor growth (pages 1418–1432). A single amino acid alteration in the pro-SF cleavage site produced uncleavable SF. When introduced into mice using an improved lentiviral vector system, uncleavable SF, through its ability to bind to both the protease and the receptor, inhibited the cleavage of normal pro-SF and the activation of Met via active SF. Local introduction of uncleavable SF into mice prevented tumorigenesis and metastases and inhibited angiogenesis. Systemic expression of uncleavable SF did not affect normal physiological functions, yet it did block implanted tumor growth and eliminate spontaneous metastases formation. This study demonstrates that pro-SF cleavage is a rate-limiting step in tumor progression, and developing mechanisms that inhibit this cleavage may lead to viable malignant cancer therapies See figure .

Version history
  • Version 1 (November 15, 2004): No description

Article tools

  • View PDF
  • Download citation information
  • Send a comment
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal

Metrics

  • Article usage
  • Citations to this article

Go to

  • Top
  • Atrophy impaired
  • Having the stomach for PAR1 activity
  • Hobbling free α-hemoglobin
  • Converging on scatter factor
  • Version history
Advertisement
Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts