JCI table of contents March 1, 2005

02/10/05

EDITORS' PICK:

Defensins ward off HIV in two ways

The body attempts to protect itself from HIV infection via the innate immune system. Defensins are proteins found in cells, which have been shown to have anti-HIV activity. However, the mechanism by which the defensins control HIV infection has not been known. Appearing online on February 17 in advance of publication in the March 1 print edition of the Journal of Clinical Investigation, Theresa Chang and colleagues from Mount Sinai School of Medicine analyze how alpha-defensin-1, in particular, inhibits HIV infection in CD4+ T cells. CD4 + T cells are white blood cells that have molecules called CD4 on their exterior. They help orchestrate the body's response to viruses and therefore play important roles in the immune system.

The researchers show that alpha-defensin-1 fights HIV in two different ways. Without serum (the watery portion of blood that remains when blood cells are removed) and under conditions where viral burden is low, alpha-defensin-1 directly inactivates HIV virus. When serum is present, alpha-defensin-1 acts on vulnerable cells to block HIV infection at the stage when the virus is taken up by the cell and begins replicating itself and integrating into the host. The authors also show that the way alpha-defensin-1 blocks HIV infection in cells is by inhibiting a CD4+ cell-signaling molecule called PKC.

The finding that alpha-defensin-1 acts on both the virus and the cell offers insights into the function of alpha-defensin-1 in innate immunity against HIV. In addition, this study provides a basis to develop defensin-like drugs for prevention of HIV and for therapeutic use in patients who are already infected.

TITLE: Alpha-defensin-1 has a dual role in anti-HIV-1 innate immunity: effects on the virion and the cell

AUTHOR CONTACT: Theresa L. Chang
Mount Sinai School of Medicine, New York, NY USA
Phone: (212) 241-6806; Fax: (212) 534-3240; E-mail: theresa.chang@mssm.edu

View the PDF of this article at: https://www.the-jci.org/press/21948.pdf

From 5:00PM USA EST Thursday February 10, 2005 a PDF of this article will be available at: http://www.jci.org/papbyrecent.shtml

RHEUMATOLOGY:

Lubricin longs to keep joints healthy

Human joints are subjected to great stress over a lifetime of use. The cartilage in a joint sustains damage resulting from friction and other forces that can wear it down. Lubricin is a protein that helps lubricate joints, but its precise function there was unknown. Appearing online on February 17 in advance of publication in the March 1 print edition of the Journal of Clinical Investigation, Matthew Warman and colleagues from Case Western Reserve University created mice lacking lubricin in order to better study its physiological function. The researchers pinpoint two ways that lubricin protects joints. First, lubricin preserves the cartilage surface by preventing protein deposition and protecting the cells that make cartilage. Second, lubricin controls the growth of cells in the joints. These findings are of interest to those who study joint disorders such as osteoarthritis and rheumatoid arthritis.

TITLE: The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth

AUTHOR CONTACT: Matthew Warman
Case Western Reserve University, Cleveland, OH USA
Phone: (216) 368-1681; E-mail: mlw14@case.edu

View the PDF of this article at: https://www.the-jci.org/press/22263.pdf

From 5:00PM USA EST Thursday February 10, 2005 a PDF of this article will be available at: http://www.jci.org/papbyrecent.shtml

PHYSIOLOGY:

Haven't got time for the pain

Pain medication is widely used yet many forms of chronic pain, including inflammatory pain such as that resulting from arthritis and migraine, often cannot be treated satisfactorily. Cyclooxygenase inhibitors are the treatment of choice for these pain forms and work non-specifically by blocking the production of proteins called prostaglandins. Because these drugs are associated with severe side effects, there is a need for new therapeutic targets that could allow specific pain treatment with few side effects. Appearing online on February 17 in advance of publication in the March 1 print edition of the Journal of Clinical Investigation, Hanns Ulrich Zeilhofer and colleagues have now identified the EP2 subtype of a prostaglandin receptor as a new key player and potential target in inflammatory pain. After inflammation, mice lacking EP2 exhibit short lasting pain of peripheral origin, but completely lack long-lasting central pain. The mice have subdued transmission of pain signals. The findings indicate that targeting a single prostaglandin receptor subtype, EP2, can control chronic pain, as opposed to non-specifically blocking all prostaglandin synthesis.

TITLE: Spinal Inflammatory hyperalgesia is mediated by prostaglandin E receptors of the EP2 subtype

AUTHOR CONTACT: Hanns Ulrich Zeilhofer
University of Erlangen-Nürnberg, Erlangen, Germany
Phone: -49-9131-85-26935; Fax: -49-9131-85-22774; E-mail: zeilhofer@pharmakologie.uni-erlangen.de

View the PDF of this article at: https://www.the-jci.org/press/23618.pdf

From 5:00PM USA EST Thursday February 10, 2005 a PDF of this article will be available at: http://www.jci.org/papbyrecent.shtml

PHYSIOLOGY:

RSK2 is bad to the bone

Proper bone homeostasis relies on a delicate balance between bone deposition by osteoblasts and resorption by osteoclasts. The transcription factor c-Fos modulates both of these cell types, and, when overexpressed, causes a bone cancer called osteosarcoma. c-Fos activity is regulated through phosphorylation by kinases including RSK2. Patients without active RSK2 develop Coffin Lowry syndrome (CLS) and suffer osteoporosis and other skeletal abnormalities due to reduced bone density. Appearing online on February 17 in advance of publication in the March 1 print edition of the Journal of Clinical Investigation, Erwin Wagner and colleagues have used a genetic approach to determine the role of RSK2 in normal osteoblast and osteoclast function, as well as its role in osteosarcoma development. They show that RSK2 deficiency decreases c-Fos stability and osteoblast function, leading to decreased bone deposition and mineralization.

The loss of RSK2 also reduced tumor burden and growth in c-Fos overexpressing mice. Hence, phosphorylation by RSK2 is essential for the oncogenic functions of c-Fos in vivo. These data provide novel insights into how deregulation of RSK2 could be involved in the development of two osteoblast-mediated pathologies, namely the osteopenia observed in CLS as well as the progression of osteosarcomas when c-Fos activity is abnormally high. This work also underlines the potential of developing molecules interfering with RSK2 signaling or c-Fos phosphorylation as new therapeutic tools for the treatment of bone diseases.

TITLE: Essential role of RSK2 in c-Fos-dependent osteosarcoma development

AUTHOR CONTACT: Erwin F. Wagner
Research Institute of Molecular Pathology, Vienna, Austria
Phone: 43-1-797-30-888; Fax: 43-1-798-9390; E-mail: Wagner@imp.univie.ac.at

View the PDF of this article at: https://www.the-jci.org/press/22877.pdf

From 5:00PM USA EST Thursday February 10, 2005 a PDF of this article will be available at: http://www.jci.org/papbyrecent.shtml

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