JCI table of contents: July 27, 2006

EDITOR'S PICK
Researchers reveal how long-term use of anti-inflammatory medication can cause osteoporosis

The steroid hormones glucocorticoids (GCs) are used at high doses to treat inflammatory and immune disorders, however they prompt bone loss and can cause osteoporosis, particularly when administered for prolonged periods. In a study appearing online on July 27 in advance of print publication in the August issue of the Journal of Clinical Investigation, Steven Teitelbaum and colleagues from Washington University School of Medicine investigated how GCs alter the activity of the bone-forming and bone-degrading cells known as osteoblasts and osteoclasts, respectively.

The authors compared the effects of the GC dexamethasone (commonly used to treat rheumatoid arthritis) on bone-degrading osteoclasts and their precursors cells from healthy mice, with its effects on the same cells derived from mice with disruption of the GC receptor. In healthy mice they found that while the steroid prolonged the longevity of osteoclasts, their bone-degrading capacity was suppressed. In mice lacking the GC receptor, no such effects were observed. It was previously known that bone degradation by osteoclasts stimulated new bone formation by osteoblasts. The results of the current study indicate that it is the GC-induced delay in the death of osteoclasts that dampens osteoblast activity and as such retards new bone formation, resulting in GC-induced osteoporosis.

TITLE: Glucocorticoids suppress bone formation via the osteoclast

AUTHOR CONTACT:

Steven L. Teitelbaum
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 454-8463; Fax: (314) 454-5505; E-mail: teitelbs@wustl.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28084

EDITOR'S PICK
Cerebrospinal fluid used to deliver therapeutics for Lou Gehrig's disease to brain

Researchers from the University of California, San Diego have shown that instead of trying to deliver therapeutic agents for neurodegenerative diseases across the highly impermeable blood-brain barrier via the blood, therapeutic molecules known as antisense oligonucleotides can be delivered to the brain and spinal cord through the cerebrospinal fluid (CSF) at doses shown to slow the progression of amyotrophic lateral sclerosis (ALS), also referred to as Lou Gehrig's disease, in rats.

The aggregation of toxic proteins in the central nervous system (CNS) underlies many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and ALS. Several strategies for removing excess proteins from the brain have been tried, but few have been successful due to the impermeability of the protective blood-brain barrier, which prevents substances in the blood from entering brain tissue. In a study in rats appearing online on July 27 in advance of print publication in the August issue of the Journal of Clinical Investigation, Timothy Miller, Richard Smith, and colleagues delivered effective doses of antisense oligonucleotides throughout all brain regions affected in the major neurodegenerative diseases and to all levels of the spinal cord through the CSF. Once produced, CSF circulates from the brain to all regions of the CNS, yielding complete replacement 3 times a day. Exploiting this process and using second-generation oligonucleotides with enhanced tolerability and potency, the authors were able to modulate and deliver effective doses of antisense oligonucleotides. Antisense oligonucleotides to the enzyme superoxide dismutase reduced protein and mRNA levels in the CNS. Delivery of antisense therapy initiated after the onset of symptoms slowed disease progression in a rat model of ALS. This establishes that direct delivery of antisense oligonucleotides through the CSF can be an effective means of treating neurodegenerative diseases when the appropriate toxic protein is known.

TITLE: Antisense oligonucleotide therapy for neurodegenerative disease

AUTHOR CONTACT:

Timothy Miller
University of California, San Diego, La Jolla, California, USA.
Phone: (858) 534-7899; Fax: (858) 534-7659; E-mail: timiller@ucsd.edu.

Richard A. Smith
Ludwig Institute for Cancer Research, La Jolla, California, USA.
Phone: (858) 455-5463; Fax: (858) 455-1713; E-mail: r8smith@ucsd.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=25424

VIROLOGY
Vaginal microbicide protects against sexually transmitted infection

Researchers have been striving to develop a topical microbicide – a gel, cream, or foam that is applied vaginally or rectally to prevent sexually transmitted infections such as HIV and herpes. Vaginal application of CpG oligodeoxynucleotides (ODNs) has been previously reported to protect mice from genital herpes infection, however the mechanism by which these agents provide protection remained unclear.

In a study in mice appearing online on July 27 in advance of print publication in the August issue of the Journal of Clinical Investigation, Akiko Iwasaki and Hong Shen from Yale University show that plasmacytoid dendritic cells (pDCs) are required for CpG ODN–mediated protection against vaginal infection with herpes simplex virus-2 (HSV-2). They go on to show that in order to be protected against infection, hematopoietic and stromal cells must respond to CpG via Toll-like receptors and type I interferons. The study suggests that the targeting of CpG ODNs to pDCs and cells lining the vaginal wall, in a time and location–specific manner, can potentially maximize the efficacy of the microbicide while minimizing any inflammation associated with application.

TITLE: A crucial role for plasmacytoid dendritic cells in antiviral protection by CpG ODN–based vaginal microbicide

AUTHOR CONTACT:

Akiko Iwasaki
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: (203) 785-2919; Fax: (203) 737-1764; E-mail: akiko.iwasaki@yale.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28681

GASTROENTEROLOGY
Understanding the immune response to forbidden foods in celiac disease

Individuals who suffer from the chronic autoimmune condition celiac disease possess serum antibodies to gluten, a protein found in wheat, barley and rye, causing a wasting away of the small intestine and poor absorption of nutrients. Currently, the only effective treatment is the life-long elimination of gluten from the diet. Antibodies to the enzyme tissue transglutaminase are found in an overwhelming majority of cases, and cross-react to gluten. This reaction occurs almost exclusively in patients with the human leukocyte antigen types HLA-DQ2 and HLA-DQ8. Over 95% of celiac patients carry 1 or 2 of the HLA-DQ2 or HLA-DQ8 genes.

In a study appearing online on July 27 in advance of print publication in the August issue of the Journal of Clinical Investigation, Ludvig Sollid and colleagues from the University of Oslo used intestinal T cells from celiac patients to locate DQ2 and DQ8 binding sites (known as epitopes) within 2 gluten proteins – alpha-gliadin and gamma-gliadin. The authors show that DQ2 and DQ8 are preferentially triggered by deamidated peptides and have a preference for binding to negatively charged residues in the gluten proteins. In addition, the authors examine the similarities and differences between peptides recognized by these two molecularly distinct DQ molecules and their association with disease susceptibility. These insights will aid our understanding of the immunopathology of celiac disease and are broadly relevant to the mechanisms of immune recognition at work in other autoimmune diseases.

TITLE: HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease

AUTHOR CONTACT:

Ludvig M. Sollid
University of Oslo, Norway.
Phone: 47-230-73811; Fax: 47-230-73510; E-mail: l.m.solid@medisin.uio.no.

View the PDF of this article at: https://www.the-jci.org/article.php?id=27620

PULMONARY
Connexin conducts cell-to-cell conversations in the inflamed lung

Severe lung inflammation, which can cause acute lung injury in cases of sepsis and infection, is associated with the accumulation in the lung and surrounding blood vessels of fluid, cells, and cellular debris. The deposition of inflammatory exudates spreads rapidly and can soon involve the entire lung or both lungs. The mechanisms underlying the spread of inflammation across the vast vascular network in the lung has remained unexplained, until now.

In a study in mice and rats appearing online on July 27 in advance of print publication in the August issue of the Journal of Clinical Investigation, Kaushik Parthasarathi and colleagues from Columbia University demonstrate a dominant role for the protein connexin 43 in transmitting proinflammatory calcium signals from endothelial cell to endothelial cell lining blood vessels in the lung. They show that connexin 43 is capable of transmitting a proinflammatory signal from small capillaries to larger blood vessels. Further investigation of this signaling pathway may reveal ways in which to reduce the spread of lung inflammation.

TITLE: Connexin 43 mediates spread of Ca2+-dependent proinflammatory responses in lung capillaries

AUTHOR CONTACT:

Kaushik Parthasarathi
Columbia University, New York, New York, USA.
Phone: (212) 523-7310; Fax: (212) 523-8005; E-mail: kp257@columbia.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=26605

CARDIOVASCULAR BIOLOGY
ACE-ing the test of blood pressure regulation

Angiotensin converting enzyme 2 (ACE2) is expressed at its highest levels in the kidney and heart, suggesting a potential role in the regulation of the cardiovascular system.

In a study appearing online on July 27 in advance of print publication in the August issue of the Journal of Clinical Investigation, Thomas Coffman and colleagues from Duke University explored the physiological role of ACE2 by studying the effects of targeted disruption of the Ace2 gene in mice. The authors show that ACE2 plays a nonredundant role in the regulation of blood pressure through its actions to metabolize Angiotensin II, which is known to cause profound constriction of blood vessels with a resulting increase in blood pressure. Interestingly, in contrast to previous reports the researchers found no evidence that ACE2 plays a major role in the regulation of cardiac structure and function.

TITLE: Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice

AUTHOR CONTACT:

Thomas M. Coffman
Duke University and Durham VA Medical Centers, Durham, North Carolina, USA.
Phone: (919) 286-6947; Fax: (919) 286-6879; E-mail: tcoffman@acpub.duke.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=16980

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Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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That which does not kill me makes me stronger.
-- Frederick Nietzsche