EDITOR'S PICK
Role of TRPM8 in the development of prostate cancer
Recent studies have indicated that the protein known as TRPM8 plays an important role in prostate cancer: high levels of TRPM8 have been found in prostate carcinoma compared to normal prostate epithelial cells, and TRPM8 has been suggested as a specific marker and therapeutic target in prostate cancer. However, the regulation of and changes in TRPM8 during prostate cancer progression have remained unclear.
In normal prostate epithelium, cells coexist in many stages of development/differentiation – progressing from stem cells to mature luminal cells. Disrupted or dysregulated differentiation and proliferation are major causes of cancer. In a study appearing online on May 17 in advance of publication in the June print issue of the Journal of Clinical Investigation, Natalia Prevarskaya from Université des Sciences et Technologies de Lille, France, show that only mature, differentiated human prostate primary epithelial luminal cells express functional plasma membrane TRPM8 (PM-TRPM8) and that prostate cancer cells possessed higher PM-TRPM8 levels than normal cells. However, endoplasmic reticulum TRPM8 (ER-TRPM8) retained it’s function as a calcium release channel, independent of the differentiation state of the cell, and may be an important factor in controlling the growth of prostate cancer cells. The authors hypothesize that the constant activity of ER-TRPM8 may be the result of the expression of a truncated form of TRPM8. The authors suggest that specific inhibition of ER-TRPM8 or PM-TRPM8 may prove to be of therapeutic use in the treatment of prostate cancer, depending on the stage of the tumor.
TITLE: Prostate cell differentiation status determines transient receptor potential melastatin member 8 channel subcellular localization and function
AUTHOR CONTACT:
Natalia Prevarskaya
Université des Sciences et Technologies de Lille, France.
Phone : 33-3-20-43-40-77; Fax: 33-3-20-43-40-66; E-mail: natacha.prevarskaya@univ-lille1.fr
View the PDF of this article at: https://www.the-jci.org/article.php?id=30168
BONE BIOLOGY
Blocking aggrecanase-2 activity prevents cartilage erosion in arthritis
The protein aggrecan comprises up to 10% of the dry weight of the cartilage in our joints, and aggrecan breakdown by enzymes known as aggrecanases occurs in arthritis. Aggrecanases cleave aggrecan at two sites within the protein – at a site within the CS-2 domain and at a second site in the interglobular domain (IGD). Recently, the enzyme aggrecanase-2 was identified as the predominant aggrecanase in mouse cartilage, however researchers were unable to distinguish aggrecanase-2 activity at the CS-2 domain from that at the IGD. In order to assess the contribution of this specific cleavage to cartilage destruction, Amanda Fosang and colleagues from the University of Melbourne created mice with a mutation that made the IGD resistant to aggrecanase. They found that blocking cleavage in the IGD diminished the loss of aggrecan and cartilage erosion in animals with osteoarthritis and inflammatory arthritis. In addition, this blockade appeared to stimulate cartilage repair following acute inflammation. The authors concluded that blocking aggrecanase-mediated cleavage in the aggrecan IGD alone was sufficient to protect against cartilage erosion in arthritis and may contribute to cartilage repair. The study appears online on May 17 in advance of publication in the June print issue of the Journal of Clinical Investigation.
TITLE: Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair
AUTHOR CONTACT:
Amanda J. Fosang
University of Melbourne and Murdoch Children’s Research Institute, Parkville, Victoria, Australia.
Phone : 61-3-8341-6466; Fax: 61-3-9345-7997; E-mail: amanda.fosang@mcri.edu.au
View the PDF of this article at: https://www.the-jci.org/article.php?id=30765
HEMATOLOGY
Keeping red blood cells hydrated in sickle cell disease
Sickle cell anemia is the most common inherited blood disorder in the United States. The transport of potassium (K) and chloride (Cl) ions in and out of red blood cells is a major determinant of the cells’ volume and density. Overactivation of K-Cl cotransport out of red blood cells leads to red blood cell dehydration and distortion (sickling).
In a study appearing online on May 17 in advance of publication in the June print issue of the Journal of Clinical Investigation, Thomas Jentsch and colleagues from Universität Hamburg investigated the role of K-Cl cotransport activity in red blood cell volume. The authors generated mice lacking the K-Cl cotransporters Kcc1 and Kcc3. As red blood cell K-Cl cotransport activity was unchanged in mice lacking Kcc1, decreased in mice lacking Kcc3, and almost completely lost in mice lacking both Kcc1 and Kcc3, the authors concluded that K-Cl cotransport in red blood cells is largely mediated by Kcc3. The authors went on to show that disruption of both K-Cl cotransporters in a mouse model of sickle cell disease was able to partially rescue the cells from dehydration. However, the proportion of the densest red blood cells remained unaffected. This result, if extrapolated to human sickle disease, predicts that inhibitors of K-Cl cotransport, if used alone, would not be maximally effective in reversing the red cell dehydration that causes sickling.
TITLE: Disruption of erythroid K-Cl cotransporters alters erythrocyte volume and partially rescues erythrocyte dehydration in SAD mice
AUTHOR CONTACT:
Thomas J. Jentsch
Universität Hamburg, Hamburg, Germany.
Phone : 49-30-9406-2961; Fax: 49-30-9406-2960; E-mail: Jentsch@fmp-berlin.de
Christian A. Hübner
Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
Phone: 49-3641-9325001; Email: christian.huebner@med.uni-jena.de
View the PDF of this article at: https://www.the-jci.org/article.php?id=30630
METABOLIC DISEASE
Enzymes and exercise curb muscle insulin resistance
An oversupply of fatty acids plays a key role in the development of insulin resistance in the skeletal muscle of obese individuals. Two related studies appearing online on May 17 in advance of publication in the June print issue of the Journal of Clinical Investigation show that exercise and expression of the enzyme diacylglycerol acyltransferase 1 (DGAT1) have important effects on the development of insulin resistance.
In the first of these two studies, Simon Schenk and Jeffrey Horowitz from the University of Michigan have shown that a single session of endurance exercise on a treadmill was sufficient to prevent insulin resistance in healthy, non-obese women. The authors showed that exercise triggered a corresponding increase in triglyceride synthesis within skeletal muscle as well as a parallel increase in the expression of the enzymes DGAT1 and mitochondrial glycerol-3-phosphate acyltransferase (mGPAT). By directing more fatty acids towards triglyceride synthesis within muscle, toxic fatty acid metabolite accumulation was reduced, which protected against fatty acid–induced insulin resistance. The study suggests that regularly performed endurance exercise may help improve insulin resistance in people with excess levels of available fatty acid, such as those with obesity.
In a related study, Yi-Hao Yu and colleagues from Columbia University also observed an increase in DGAT1 activity in skeletal muscle and that fatty acids were channeled into triglycerides following exercise. In addition, the author studied mice that overexpressed DGAT1 in skeletal muscle and found that they were protected against high-fat diet–induced insulin resistance. The data illustrate how exercise can enhance muscle insulin sensitivity and the authors suggest that increasing muscle DGAT activity may offer a potential new approach to prevent and treat insulin resistance in type 2 diabetes.
TITLE: Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid–induced insulin resistance
AUTHOR CONTACT:
Jeffrey F. Horowitz
University of Michigan, Ann Arbor, Michigan, USA
Phone: (734) 647-1076; Fax: (734) 936-1925; E-mail: jeffhoro@umich.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=30566
RELATED ARTICLE:
TITLE: Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance
AUTHOR CONTACT:
Yi-Hao Yu
Columbia University, New York, New York, USA
Phone: 212-305-2068; Fax: (212) 305-3213; E-mail: yy102@columbia.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=30565
VASCULAR BIOLOGY
Endothelial progenitor cells mend vessel damage with a little help from EphB4
Vascular disease is a major heath problem in Western countries and poor oxygen delivery to tissues results can result in ischemia, gangrene, and the need to amputate. The transplantation of endothelial progenitors cells (EPCs) is capable of boosting new blood vessel growth in ischemic tissues, however this approach has been limited by the fact that few of the injected cells accumulate at sites of tissue damage. In a study appearing online on May 17 in advance of publication in the June print issue of the Journal of Clinical Investigation, Gérard Tobelem and colleagues from Institut des Vaisseaux et du Sang, Paris, report a way in which the potential of EPCs to form new blood vessels can be enhanced.
During vessel development, 2 proteins – EphB4 and ephrin-B2 – are expressed in the endothelium that lines blood vessels. Tobelem et al. showed that EphB4 activation with an ephrin-B2-Fc chimeric protein enhanced EPC activation and new vessel growth in the ischemic hind limbs of mice. This was due to enhanced EPC adhesion to the vessel wall. The authors conclude that activation of EphB4 is an innovative and potentially valuable therapeutic strategy for improving the recruitment of EPCs to sites of tissue ischemia and in doing so boosting the efficiency of cell-based therapies for vascular disease.
TITLE: PSGL-1–mediated activation of EphB4 increases the proangiogenic potential of endothelial progenitor cells
AUTHOR CONTACT:
Gérard Tobelem
Institut des Vaisseaux et du Sang, Paris, France.
Phone : 33-1-45-26-21-98; Fax : 33-1-42-82-94-73; E-mail: gerard.tobelem@lrb.aphp.fr
View the PDF of this article at: https://www.the-jci.org/article.php?id=28338
AUTOIMMUNITY
B cell immunoglobulins and a change that will do you no good
The diversity and efficiency of mechanisms by which the immune system combats infection results in a delicate balance between protection and immune reactivity to our own normal tissues. A better understanding of the origin and fate of B cells, which have the ability to generate dangerous autoantibodies that cause autoimmune diseases such as lupus and arthritis, is needed.
Mature B cells that have not been exposed to foreign antigens make immunoglobulin (Ig) M and IgD antibodies. After activation, these B cells can be induced to switch the class of Ig that they make by replacement of IgM and IgD with IgG, IgA, or IgE – a phenomenon known as “class switching”. In less than 3% of B cells, IgM is lost, but IgD is retained, forming Cdelta-CS B cells. In a study appearing online on May 17 in advance of publication in the June print issue of the Journal of Clinical Investigation, Patrick Wilson and colleagues from Oklahoma Medical Research Foundation report that Cdelta-CS B cells are highly reactive to self antigens. Future studies will be important to determine the mechanism by which the majority of Cdelta-CS B cells are autoreactive and may provide insight into the enigmatic function of the IgD antibody, with the goal of understanding the action of autoreactive B cells in autoimmune disease.
TITLE: Mature B cells class switched to IgD are autoreactive in healthy individuals
AUTHOR CONTACT:
Patrick C. Wilson
Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Phone : (405) 271-7393 ext. 34556; Fax: (405) 271-8237; E-mail: wilsonp@omrf.ouhsc.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=27628
Journal
Journal of Clinical Investigation