EDITOR'S PICK:
Double trouble for RA patients: PLC-gamma-2 regulates osteoclastogenesis and B cell differentiation
Rheumatoid arthritis (RA) is best known as a chronic inflammatory disease caused by the immune system inappropriately attacking the joints. However, the autoimmune response also leads to the recruitment and/or differentiation of cells known as osteoclasts -- which are cells that degrade and resorb bone. Current treatments for patients with RA target either the joint-specific immune response or the osteoclast-mediated bone erosion.
Now, in a study appearing online on October 19 in advance of publication in the November print issue of the Journal of Clinical Investigation, researchers from Washington University have shown that the protein PLC-gamma-2, which was already known to regulate the differentiation of B cells (one of the immune cells crucial to the autoimmune response seen in RA), is required for normal osteoclast development and function in mice. Roberta Faccio and colleagues therefore suggest that targeting PLC-gamma-2 might lead to control of both the immune-mediated joint destruction and osteoclast-mediated bone erosion seen in RA.
TITLE: PLC-gamma-2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2
AUTHOR CONTACT:
Roberta Faccio
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 747-4602; Fax: (314) 362-0334; E-mail: faccior@wustl.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28775
VASCULAR BIOLOGY: Role for NF-kappa-B in endothelial cell function
Sepsis is a life-threatening disease that can occur during bacterial or viral infection of the blood. It can cause the barrier between the blood and the surrounding tissues, which is formed by cells known as endothelial cells, to become severely damaged, allowing the blood to seep out into the tissues and the blood pressure to drop dramatically. Conversely, tumors promote the proliferation and growth of endothelial cells so that the tumor has its own blood supply that supplies it with nutrients for growth. Therefore, understanding how endothelial cell function is regulated is an area of intensive investigation.
In a study appearing online on October 19, in advance of publication in the November print issue of the Journal of Clinical Investigation, Christian Schindler and colleagues from Columbia University, New York, show that in mice a regulator of gene expression known as NF-kappa-B controls endothelial cell function in a model of shock and in a model of cancer. Mice expressing an inhibitor of NF-kappa-B only in endothelial cells were more susceptible to sepsis induced by administration of the bacterial product LPS than normal mice. In addition, tumors grew more rapidly in these mice than in normal mice. This study implicates NF-kappa-B as a regulator of endothelial cells function in health and disease, leading the authors to suggest that care should be taken when developing therapeutic inhibitors of NF-kappa-B as they might have hitherto unforeseen effects on endothelial cells.
TITLE: NF-kappa-B regulation of endothelial cell function during LPS-induced toxemia and cancer
AUTHOR CONTACT:
Christian Schindler
Columbia University, New York, New York, USA.
Phone: (212) 305-5380; Fax: (212) 543-0063; E-mail: cws4@columbia.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27392
ONCOLOGY: CYLD puts a damper on inflammation
Familial cylindromatosis is a disease characterized by the presence of numerous tumors of the hair follicles and sweat glands of the head and neck. Individuals with this disease have mutations in their genes encoding a protein known as CYLD and express shortened forms of this protein. However, the function of CYLD and why defects in CYLD lead to tumors has not been determined. Now, in a study appearing online on October 19, in advance of publication in the November print issue of the Journal of Clinical Investigation, researchers from the National Institutes of Health, have shown that in mice CYLD limits inflammation and tumor formation.
Ashish Jain and colleagues showed that mice lacking CYLD developed inflammation of many organs (including the liver and lungs) as they aged, and developed more severe inflammation and more tumors in their colon than normal mice in a mouse model of inflammation-induced colon cancer. Increased inflammation was a result of increased activity of a signaling molecule crucial to the induction of inflammatory responses, NF-kappa-B, and this occurred because the activity of proteins that activate NF-kappa-B was not downregulated. This study shows that CYLD is an important regulator of a signaling pathway that controls inflammation and inflammation-induced tumor formation, and suggests that CYLD functions as a tumor suppressor.
TITLE: Impaired regulation of NF-kappa-B and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient mice
AUTHOR CONTACT:
Ashish Jain
National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
Phone: (301) 594-5691; Fax: (301) 402-2240; E-mail: ajain@niaid.nih.gov.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28746
PULMONARY: TLR4 performs a balancing act in the lungs
Emphysema is a chronic lung disease that causes severe shortness of breath. It is characterized by a gradual loss of lung elasticity and irreversible airspace enlargement. Maintaining the correct balance of oxidants and antioxidants is crucial to maintaining the structure of the lungs, but exactly how this is done is not well defined. Now, in a study appearing online on October 19 in advance of publication in the November print issue of the Journal of Clinical Investigation, Patty Lee and colleagues from Yale University, have shown that as mice lacking the immune receptor TLR4 age their lungs resemble the lungs of individuals with emphysema. Expression of TLR4 in the epithelial cells of the lungs was shown to be required for maintaining the structure of the lungs by limiting expression of a protein known as NOX3. NOX3 generates oxidants and in the absence of TLR4, the oxidant–antioxidant balance in the lungs was tipped toward oxidants, leading to increased emphysema. This study provides new insight into the mechanisms by which emphysema develops, but further work is required to determine how the shift in the oxidant–antioxidant balance results in destruction of the structure of the lungs.
TITLE: Toll-like receptor 4 deficiency causes pulmonary emphysema
AUTHOR CONTACT:
Patty J. Lee
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: (203) 785-5877; Fax: (203) 785-3826; E-mail: patty.lee@yale.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28139
METABOLIC DISEASE: Triggering TLR4 can raise resistance to insulin
Type 2 diabetes is caused by insulin resistance, which occurs when cells do not respond to insulin causing the storage and release of energy to become dysregulated. Obesity is linked to insulin resistance, but the mechanisms involved have been hard to characterize -- although some studies have indicated a role for inflammation. Now, in a study appearing online on October 19 in advance of publication in the November print issue of the Journal of Clinical Investigation, researchers from Beth Israel Deaconess Medical Center, Boston, have found a link between obesity, inflammation, and insulin resistance.
Jeffrey Flier and colleagues found that free fatty acids, levels of which are increased in individuals who are obese, triggered an inflammatory response in several mouse cell types in vitro. This response was decreased if the cells expressed decreased amounts of an immune receptor known as TLR4. Furthermore, mice lacking TLR4 were markedly protected from insulin resistance induced by infusion of fats and were partially protected from insulin resistance induced by feeding on a high fat diet. This study identifies TLR4 as one component of the link between obesity, inflammation, and insulin resistance.
TITLE: TLR4 links innate immunity and fatty acid–induced insulin resistance
AUTHOR CONTACT:
Jeffrey S. Flier
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Phone: (617) 667-9050 Fax: (617) 667-9054; E-mail: jflier@bidmc.harvard.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28898
BONE BIOLOGY: Hyperactive osteoclasts cause osteoporosis in neurofibromatosis type 1 patients
Neurofibromatosis type 1 (NF1) is a relatively common genetic disorder (around 1 per 3,000 births) caused by inheriting one mutated copy of the gene NF1. Individuals with NF1 exhibit a range of symptoms, the most severe of which are tumors that grow along certain types of nerves. However, other symptoms, including osteoporosis, are also seen in some individuals.
To understand why individuals expressing only one copy of NF1 (NF1+/-) develop osteoporosis, Wade Clapp and colleagues from Indiana University generated mice expressing only one copy of Nf1 (Nf1+/- mice). Nf1+/- mice were found to have increased numbers of osteoclasts, which are cells that degrade and resorb bone. These osteoclasts were better at surviving, proliferating, and degrading bone than osteoclasts from normal mice. These abnormal characteristics were associated with increased activity of two signaling molecules, p21ras and PI3K. Importantly, in this study, which appears online on October 19 in advance of publication in the November print issue of the Journal of Clinical Investigation, it was shown that osteoclasts from individuals with NF1 have the same characteristics as osteoclasts from Nf1+/- mice. This study not only provides insight into why individuals with NF1 suffer from osteoporosis, but also leads the authors to suggest that targeting PI3K might be a viable therapy for treating all individuals with osteoporosis.
TITLE: Hyperactivity of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1–haploinsufficient osteoclast functions
AUTHOR CONTACT:
D. Wade Clapp
Indiana University School of Medicine, Indianapolis, Indiana, USA.
Phone: (317) 278-9290; Fax: (317) 274-8679; E-mail: dclapp@iupui.edu.
Feng-Chun Yang
Indiana University School of Medicine, Indianapolis, Indiana, USA.
Phone: (317) 278-9290; Fax: (317) 274-8679; E-mail: fyang@iupui.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29092
Journal
Journal of Clinical Investigation