Increased bone mass in a calcitonin knockout mouse full of surprises
Bone is in a constant state of remodeling, during which osteoclasts remove old bone (resorption) and osteoblasts form new bone (formation). Calcitonin is a hormone produced by the thyroid gland and inhibits bone resorption. Following menopause, the rate of bone loss is accelerated, however women with post-menopausal osteoporosis that are treated with calcitonin (by injection or nasal spray) demonstrate increased bone mass and strength, in addition to a decrease in the rate of bone fractures. Following alternative processing, the gene encoding calcitonin (CT/CGRP) also encodes a second peptide: calcitonin gene-related peptide-a (CGRPa), however the role of this peptide in bone metabolism has not been clearly defined.
To better understand the role of calcitonin and CGRP-a in bone metabolism Robert Gagel and colleagues at the University of Texas M.D. Anderson Cancer Center, USA, created mice in which the CT/CGRP gene had been deleted. Given that both calcitonin and CGRP have been shown to inhibit bone resorption and CGRP is known to stimulate bone formation, the authors predicted that there would be either no effect of this deletion on bone mass, or there could be some bone loss.
In the December 16 issue of the Journal of Clinical Investigation, the authors report their surprising finding that CT/CGRP-deficient mice have greater bone mass, increased bone formation, and were able to maintain bone mass during estrogen deficiency by increasing bone formation. These findings suggest an important and novel function for the products of the CT/CGRP gene, that was previously unrecognized. They also suggest that the development of an antagonist to the CT/CGRP gene product(s) may be useful in the prevention of bone loss associated with estrogen deficiency.
Mone Zaidi and colleagues from the Mount Sinai Bone Program at Mount Sinai Hospital, New York, discuss these surprising findings in their accompanying commentary.
CONTACT:
Robert F. Gagel
The University of Texas M.D. Anderson Cancer Center
Department of Endocrine Neoplasia and Hormonal Disorders
1400 Holcombe Blvd.
Box 433
Houston, TX 77030
USA
Phone: 713-792-6517
Fax: 713-794-1818
E-mail: rgagel@mdanderson.org
View the PDF of this article at: https://www.the-jci.org/press/14218.pdf
ACCOMPANYING COMMENTARY: Calcitonin and bone formation: a knockout full of surprises
CONTACT:
Mone Zaidi
Mount Sinai School of Medicine
Annenberg 5, PO 1055
Division of Endocrinology
One Gustave Levy Place
New York, NY 10029
USA
Phone: 212-241-8797
Fax: 212-426-8312
E-mail: mone.zaidi@mssm.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17425.pdf
TABLE OF CONTENTS
The hepatitis B virus X protein promotes tumor cell invasion by inducing Membrane-type matirx metalloproteinase and cyclooxygenase-2 expression
Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma, a cancer associated with recurrent intrahepatic metastasis and poor prognosis. HBx is the only viral gene product consistently present in hepatic tumor cells, and previous work has focused mainly on its potential role in tumor development. Manuel López-Cabrera and colleagues, in contrast, have studied the role of HBx in metastasis. As they report on pages 1831-1838, HBx expression induces tumor cell invasion in vitro and in vivo. The invasive phenotype is associated with increased levels of cyclooxygenase-2 (COX-2) and matrix metalloproteinases and can be blocked by COX-2 inhibitors. HBx, a transcriptional activator, upregulates COX-2 expression at the mRNA and protein levels. These results suggest that HBx plays a direct role in the late stages of hepatocellular carcinoma.
CONTACT:
Manuel López-Cabrera
Hospital Universitario de la Princesa
Unidad de Biologia Molecular, Hospital Universitario de la Princesa, Diego
Madrid, NULL 28006
SPAIN
Phone: 34-91-5202334
Fax: 34-91-5202374
E-mail: mlopez@hlpr.insalud.es
View the PDF of this article at: https://www.the-jci.org/press/15887.pdf
Targeted disruption of H3 receptor results in changes in brain histamine tone leading to obese phenotype
Histamine has numerous functions in the mammalian immune, digestive, and nervous systems. Previous studies suggested that histamine may regulate food intake, a function most likely mediated by H3 receptors in the hypothalamus. Hidehito Kotani and colleagues have directly tested this hypothesis by generating and analyzing mice lacking H3 receptors. As they report (pages 1791-1799), the mutant animals are mildly obese, have increased food intake and adipodisity, and also have reduced energy expenditure. In addition, they have increased levels of plasma leptin and insulin, exhibit resistance to both hormones, and show decreased levels of histamine and increased histamine turnover in the hypothalamic and thalamic brain regions. These results demonstrate a critical role of H3 receptors in the control of body weight in mice.
CONTACT:
Hidehito Kotani
Banyu Tsukuba Research Institute
3 Okubo
Tsukuba
Ibaraki 300-2611,
JAPAN
Phone: 81-298-77-2202
Fax: 81-298-77-2027
E-mail: kotanihh@banyu.co.jp
View the PDF of this article at: https://www.the-jci.org/press/15784.pdf
Collagen-binding integrin [alpha]1[beta]1 regulates intestinal inflammation in experimental colitis
Inflammatory bowel diseases are associated with chronic inflammation of the intestinal tract. Affected tissue is characterized by dense leukocyte infiltrate, and therapeutic strategies to interfere with adhesion molecules necessary for leukocyte migration and activation are under investigation. Antonin de Fougerolles and colleagues have focused on the collagen-binding integrin [alpha]1[beta]1, which is expressed on the surface of activated T cells and monocytes. They report (pages 1773-1782) that lack of alpha1beta1 integrin or its blockage with antibody attenuated disease in a mouse model of colitis. This effect occurred independently of lymphocytes, and [alpha]1[beta]1-expressing monocytes were identified as a key cell type involved in the development of colitis in this model. These results underscore the importance of innate immunity in addition to the interaction of leukocytes with the extracellular matrix in regulating local inflammatory responses.
CONTACT:
Antonin R. de Fougerolles
Biogen, Inc.
12 Cambridge Center
Cambridge, MA 02142
USA
Phone: 617-679-3205
Fax: 617-679-3148
E-mail: tony_de_fougerolles@biogen.com
View the PDF of this article at: https://www.the-jci.org/press/15256.pdf
Removal of anti-Gal[alpha]1,3Gal Xenoantibodies with an Injectable polymer
Pig cells, unlike those of humans and Old World primates, express a specific trisaccharide ([alpha]Gal) on their surfaces, and antibody-mediated destruction of donor tissues is a major hurdle of pig-to-primate organ transplantation. One way to avoid this problem is to sequester the circulating [alpha]Gal antibodies and thus prevent them from binding to and destroying the donor tissue. Andreas G. Katopodis and colleagues developed a soluble [alpha]Gal-polylysine conjugate (called GAS914) that effectively competes with cell-surface aGal for antibody binding. On pages 1869-1877 the authors report that in different monkey species, injections of GAS914 drastically reduced the levels of circulating aGal antibodies and anti-pig cytotoxicity. The conjugate binds to circulating antibodies, and the complex is quickly metabolized and excreted without apparent acute or chronic toxicity. The GAS backbone may be a promising scaffold to which to attach other antigens for the antigen-specific removal of antibodies in vivo.
CONTACT:
Andreas Katopodis
Novartis Transplantation Research
WSJ-386.6.45
Basel, NULL 4002
SWITZERLAND
Phone: 41-61-324-4861
E-mail: andreas.katopodis@pharma.novartis.com
View the PDF of this article at: https://www.the-jci.org/press/16526.pdf
Functional Repair of a Mutant Chloride Channel Using a Trans-splicing Ribozyme
Modified versions of the Tetrahymena group I intron ribozyme have been used previously to repair defective proteins in cultured cells, but the general applicability and efficiency of the process is still unclear. In an article beginning on page 1783, Alfred L. George, Jr., and colleagues demonstrate that ribozyme-mediated trans-splicing can repair a mutant chloride channel mRNA transcript. The ribozyme they engineered catalyzed trans-splicing of a 4 kb–long restorative exon (compared with 1.1 kb, the largest exon trans-spliced previously), and the repaired mRNA product is translated into a functional channel. While this is the first demonstration of complete restoration of protein function using trans-splicing ribozymes, the efficiency of the trans-splicing reaction remains a critical issue. Overall repair efficiency in the study was low, but detailed analysis revealed a striking heterogeneity among individual cells. Future experiments will need to explain that heterogeneity and might suggest ways to increase overall efficiency.
CONTACT:
Alfred George
Vanderbilt University
Division of Genetic Medicine
529 Light Hall
Vanderbilt University
Nashville, TN 37232-0275
USA
Phone: 615-936-2660
Fax: 615-936-2661
E-mail: al.george@vanderbilt.edu
View the PDF of this article at: https://www.the-jci.org/press/16481.pdf
Pregnancy Alters Glucose-6-Phosphate Dehydrogenase Trafficking, Cell Metabolism and Oxidant Release in Maternal Neutrophils
CONTACT:
Andrei Kindzelskii
Wayne State University
Detroit, MI 48202
USA
Phone: 313-577-6821
E-mail: akindzel@chem.wayne.edu
View the PDF of this article at: https://www.the-jci.org/press/15973.pdf
C5a anaphylatoxin is a major regulator of activating versus inhibitory Fc[gamma]Rs in immune complex induced lung disease
CONTACT:
J. Engelbert Gessner
Hannover Medical School
Dept. of Clinical Immunology
Carl-Neuberg Str. 1
30625 Hannover,
GERMANY
Phone: 49-511-532-3621/3919
Fax: 49-511-532-5648
E-mail: Gessner.Johannes@MH-Hannover.DE
View the PDF of this article at: https://www.the-jci.org/press/16577.pdf
ACCOMPANYING COMMENTARY: A full complement of receptors in immune complex diseases
CONTACT:
Jeffrey Ravetch
Rockefeller University
Lab Molecular Genetics and Immunology
1230 York Av. Box 98
New York, NY 10021-6399
USA
Phone: 212-327-7321
Fax: 212-327-7318
E-mail: ravetch@rockvax.rockefeller.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17349.pdf
Absence of Angiotensin II Type 1 Receptor in Bone Marrow-Derived_Cells is Detrimental in the Evolution of Renal Fibrosis
CONTACT:
Iekuni Ichikawa
Department of Pediatrics
Tokai University Hospital
Boseidai
Isehara
Kanagawa, UNK 259-1193
JAPAN
Phone: 81/463-90-1612
Fax: needed
E-mail: iekuni.ichikawa@mcmail.vanderbilt.edu
View the PDF of this article at: https://www.the-jci.org/press/15045.pdf
ACCOMPANYING COMMENTARY: Unexpected news in renal fibrosis
CONTACT:
Juan A. Oliver
Columbia University
Department of Medicine
630 West 168 Street
New York, NY 10032
USA
Phone: 212-305-6938
Fax: 212-305-3475
E-mail: jao7@columbia.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17399.pdf
Multiepitope CD8+ T cell response to a NY-ESO-1 peptide vaccine results in imprecise tumor targeting
CONTACT:
Danila Valmori
Ludwig Institute Clinical Trial Center
New York Branch at Division of Medical Oncology
Department of Medicine, Columbia University College of Physicians and Surgery
650 West 168th Street, Black Building, Room 20-22
New York, NY 10032
USA
Phone: 212-305-3923
Fax: 212-305-6798
E-mail: Danila.Valmori@inst.hospvd.ch
View the PDF of this article at: https://www.the-jci.org/press/16428.pdf
ACCOMPANYING COMMENTARY: Getting peptide vaccines to work: just a matter of quality control?
CONTACT:
Esteban Celis
Mayo Clinic
Department of Immunology
GU421A
Rochester, MN 55905
USA
Phone: 507-284-0124
Fax: 507-266-5255
E-mail: celis.esteban@mayo.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17405.pdf
The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta-cell growth
CONTACT:
Domenico Accili
Columbia University
Berrie Research Pavilion
1150 St. Nicholas Av. Room 238A
New York, NY 10032
USA
Phone: 212-304-5332
Fax: 212-304-7390
E-mail: da230@columbia.edu
View the PDF of this article at: https://www.the-jci.org/press/16857.pdf
**Please mention the Journal of Clinical Investigation as the source of these articles**
Journal
Journal of Clinical Investigation