EDITOR'S PICK: HOXA11 shows its strength in the pelvis
The quality of life of millions of women is negatively affected by pelvic organ prolapse (POP) — the downward descent of the pelvic organs that causes symptoms such as urinary incontinence. In women with POP, the uterosacral ligaments (USLs), the main supportive structures of the uterus and vagina, are attenuated. Although changes in the content and quality of the collagen in the connective tissue of USLs have been associated with POP, no molecular mechanism(s) underlying this disorder has been described. However, Kathleen Connell colleagues, at Yale University School of Medicine, New Haven, have now shown in mice that the protein encoded by the homeobox gene Hoxa11 is an essential molecular factor for the development of USLs, leading them to suggest that changes in HOXA11-regulated pathways might weaken the connective tissue of USLs and thereby cause POP.
In the study, mice lacking Hoxa11 were found to have no USLs and expression of HOXA11 was found to be markedly decreased in the USLs of women with POP. The USLs of women with POP also expressed decreased levels of the collagen type I and collagen type III genes as well as increased levels of the MMP2 gene that enables cells to generate a mediator of connective tissue degradation. Further in vitro analysis indicated that the mouse Hoxa11 gene increased expression of the collagen type III gene and decreased expression of the Mmp2 gene, thereby defining a molecular mechanism regulating the mechanical strength of USLs.
TITLE: HOXA11 is critical for development and maintenance of uterosacral ligaments and deficient in pelvic prolapse
AUTHOR CONTACT: Kathleen A. Connell Yale University School of Medicine, New Haven, Connecticut, USA. Phone: (203) 785-6927; Fax: (203) 785-2909; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34193
EDITOR'S PICK: Blinded by sFRP-1: A WNT signaling protein plays a key role in glaucoma
Glaucoma is one of the major causes of visual impairment and blindness throughout the world. A major risk factor for the disease is an increase in the pressure in the eye (intraocular pressure [IOP]). IOP is determined by the rate of production of the clear fluid in the eye and the rate at which this fluid flows out of the eye. Although it is thought that impaired outflow of fluid from the eye causes the increased IOP in individuals with glaucoma, the precise molecular mechanisms underlying the disorder are poorly understood. In a new study, Abbot Clark and his colleagues, at Alcon Research Ltd. in Fort Worth and the University of Iowa in Iowa City, have revealed that increased expression of the protein sFRP-1, an inhibitor of cell signaling through WNT proteins, seems to be responsible for elevated IOP in individuals with glaucoma.
The researchers found increased expression of sFRP-1 in eye tissue from patients with glaucoma. When donor human eyes were treated with sFRP-1 ex vivo, these eye tissues exhibited decreased outflow of fluids compared to untreated eyes. Furthermore, the sFRP-1 treated donor eyes also had reduced expression of a WNT-related protein. Finally, increased IOP was observed in mice manipulated to express sFRP-1 in the eye and this was effectively resolved by treatment with an inhibitor of a downstream suppressor of WNT signaling. The authors therefore concluded that restoring WNT signaling might be a novel way to treat individuals with glaucoma.
TITLE: Increased expression of the WNT antagonist sFRP-1 in glaucoma elevates intraocular pressure
AUTHOR CONTACT: Abbot F. Clark Alcon Research Ltd., Fort Worth, Texas, USA. Phone: (817) 551-4909; Fax: (817) 568-7645; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33871
EDITOR'S PICK: A new look inside the brain at cerebral malaria
Cerebral malaria (CM), which kills over 3 million individuals a year, is caused by infection with Plasmodium falciparum. One of the main causes of disease symptoms is the adherence of blood cells known as platelets to the small blood vessels (microvasculature) in the brain. Currently there is no way to detect such platelet accumulation until after the clinical signs of the disease are visible. However, a new way to detect platelet accumulation in the microvasculature of the mouse brain has now been developed by Daniel Anthony and colleagues at the University of Oxford, United Kingdom.
In the study, a protein (known as a single-chain antibody) that specifically binds a region of the GPIIb/IIIa receptor that is expressed only on activated platelets was attached to microparticles of iron oxide. Using this contrast reagent, it was possible to detect by magnetic resonance imaging (MRI) activated platelets in the brain of mice 6 days after they were infected with Plasmodium berghei. At this time point after infection, clinical symptoms of the disease had not appeared and activated platelets in the brain could not be detected by conventional MRI. These data led the authors to suggest that targeted contrast reagents similar to the one described in their study might prove useful for diagnostic, mechanistic, and therapeutic analyses.
TITLE: A contrast agent recognizing activated platelets reveals murine cerebral malaria pathology undetectable by conventional MRI
AUTHOR CONTACT: Daniel C. Anthony University of Oxford, Oxford, United Kingdom. Phone: 44-1865-281136; Fax: 44-1865-271853; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33314
SKELETAL MUSCLE DISEASE: X-chromosome gene linked to a muscle disorder
New data generated by Carsten Bönnemann and colleagues, at The Childrens Hospital of Philadelphia, have identified mutations in the FHL1 gene as the genetic defect in several individuals with the rare muscle disorder reducing body myopathy (RBM), which is characterized by progressive muscular weakness.
The high frequency of sporadic cases of RBM and the limited number of familial cases has made it difficult to determine the gene(s) that is mutated in individuals with this disease. To overcome these problems, the authors analyzed the protein content of the aggresome-like inclusions found in the muscles of individuals with RBM. The protein FHL1, which is normally expressed in skeletal muscle, was found to be the predominant component of the inclusions. Further genetic analysis indicated the FHL1 gene of individuals with RBM contained mutations. When one of the mutated FHL1 genes was expressed in a human skeletal muscle cell line in vitro it induced the formation of aggresome-like inclusions. As the FHL1 gene is found on the X chromosome, these data therefore led the authors to suggest that RBM is an X chromosomelinked protein aggregation disorder of muscle.
TITLE: Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy
AUTHOR CONTACT: Carsten G. Bönnemann The Childrens Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. Phone: (215) 590-7490; Fax: (215) 590-3709; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34450
HEMATOLOGY: Multiply and replenish the liver: transplanted cells correct mouse hemophilia A
Transplanting healthy cells to repair diseased, damaged, and nonfunctional organs is a major goal of cell therapy; however, the mechanisms by which transplanted cells replenish target tissue have remained elusive. A new study by Sanjeev Gupta and his colleagues, at the Albert Einstein College of Medicine in the Bronx, has determined that transplanted liver endothelial cells can be used to correct the bleeding disorder in mice with a disease that resembles hemophilia A. They found that when liver sinusoidal endothelial cells were transplanted into normal mice, the transplanted cells proliferated and replaced substantial portions of the liver endothelium of the recipient mice. Furthermore, these grafted cells successfully produced factor VIII, a key blood clotting protein that is absent or poorly produced by patients with hemophilia A. When transplanted into mice with a disease that resembles hemophilia A, the liver sinusoidal endothelial cells were able to restore factor VIII production and correct the bleeding defect. The authors therefore concluded that transplantation of healthy endothelial cells might be a viable cell therapy for certain diseases.
TITLE: Transplanted endothelial cells repopulate the liver endothelium and correct the phenotype of hemophilia A mice
AUTHOR CONTACT: Sanjeev Gupta Albert Einstein College of Medicine, Bronx, New York, New York, USA. Phone: (718) 430-2098; Fax: (718) 430-8975; E-mail: email@example.com.
MEDIA CONTACT: Karen Gardner Media Relations Manager Albert Einstein College of Medicine Bronx, New York, New York, USA. Phone: (718) 430-3101; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32748
IMMUNOLOGY: CXCR4 functional defects explained on a WHIM
Many cases of WHIM syndrome — a rare combined immunodeficiency disorder — have been linked to inherited mutations in the CXCR4 gene. These mutations lead to the generation of a CXCR4 protein that exhibits enhanced and prolonged activation of downstream signaling proteins, known as G proteins, due to an inability of CXCR4 to be uncoupled from G proteins and internalized following binding of its partner protein CXCL12. Surprisingly, a similar defect in CXCR4 function has been observed in patients with WHIM syndrome who do not have mutations in their CXCR4 gene (WHIMWT). One potential mechanism by which CXCR4 function might be altered in these WHIMWT patients has now been provided by Françoise Bachelerie and colleagues at INSERM U819 France.
In the study, it was shown that human immune cells known as leukocytes in which expression of the protein GRK3 was silenced exhibited the same defects in CXCR4 function as WHIMWT leukocytes. Consistent with the possibility that GRK3 function is impaired in WHIMWT leukocytes, overexpression of GRK3 in both leukocytes and skin fibroblasts from 2 unrelated WHIMWT patients restored CXCR4 function to normal. Furthermore, expression of the GRK3 gene was found to be decreased in cells from one WHIMWT patient. These data have identified a mechanism to explain how individuals with no mutations in their CXCR4 gene might develop WHIM syndrome.
TITLE: Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling
AUTHOR CONTACT: Françoise Bachelerie INSERM U819, Institut Pasteur, Paris, France. Phone: 33-0-1-40-61-34-67; Fax: 33-0-1-45-68-89-41; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33187
HEMATOLOGY: The protein PDI pulls the trigger to initiate blood clot formation
The formation of a blood clot prevents excessive blood loss when a blood vessel is pierced. Activation of a protein known as tissue factor (TF) is an essential part of the cascade of events that leads to blood coagulation and blood clot formation. The mechanisms by which TF is activated after blood vessels are punctured are, however, not well defined. But new data, generated in mice by Bernd Engelmann and colleagues, at Ludwig-Maximilians-Universität, Germany, now suggest that protein disulfide isomerase (PDI) might have an important role in translating blood vessel injury into blood clot formation.
In the study, it was shown that PDI was released from activated platelets at the site of injury when mouse carotid arteries were punctured. Furthermore, inhibition of PDI decreased TF activation in several mouse models of blood clot formation. Conversely, PDI infusion initiated blood coagulation. Additional in vitro analysis indicated that PDI secreted by human platelets contributed to TF activation indicating that blood coagulation might be triggered by this mechanism in humans. Further studies are, however, required to determine whether inhibiting PDI might provide a new approach to treating human conditions associated with aberrant blood clot formation such as several forms of heart diseases and strokes.
TITLE: Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activation
AUTHOR CONTACT: Bernd Engelmann Ludwig-Maximilians-Universität, Munich, Germany. Phone: 49-89-7095-3243; Fax: 49-89-7095-6220; E-mail: Bernd.Engelmann@med.uni-muenchen.de.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32376
CARDIOVASCULAR DISEASE: Renin is a potential protein target for combating high cholesterolinduced hardening of the arteries
The protein renin is a major component of the renin-angiotensin hormone system (RAS) that has a vital role in modulating blood pressure. The RAS has been implicated in the hardening of the arteries (termed atherosclerosis) caused by high levels of blood cholesterol, a condition known as hypercholesterolemia. However, the precise role of the RAS in hypercholesterolemia-induced atherosclerosis has not been completely defined. New data, generated by Alan Daugherty and colleagues, at the University of Kentucky, Lexington, have revealed that renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice.
Renin inhibition in mice with profound hypercholesterolemia was found to reduce the size of the artery hardening atherosclerotic plaques. Macrophages are cells that play a critical role in the development of atherosclerotic plaques and they were shown to produce proteins of the RAS system. Further analysis indicated that when the bone marrow of mice with hypercholesterolemia was replaced with that of renin-deficient mice, a procedure that favors the production of renin-deficient macrophages, atherosclerotic plaque sizes were reduced. The authors therefore concluded that macrophage-derived renin plays an important role in the development of atherosclerotic plaques. As the function of renin-deficient macrophages was not markedly altered and renin-expressing macrophages augmented monocyte adhesion to endothelial cells in culture, it seems probable that the effects of macrophages-derived renin are mediated on other cells, such as monocytes or endothelial cells, influencing the development of atherosclerotic plaques.
TITLE: Renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice
Alan Daugherty University of Kentucky, Lexington, Kentucky, USA. Phone: (859) 323-4933 ext. 81389; Fax: (859) 257-3646; E-mail: Alan.Daugherty@uky.edu.
Lisa A. Cassis University of Kentucky, Lexington, Kentucky, USA. Phone: (859) 323-4933 ext. 81400; Fax: (859) 257-3646; E-mail: Lcassis@uky.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32970