In a second independent study in the same issue of the Journal of Clinical Investigation, Rajiv Kumar and colleagues at the Mayo Clinic in Rochester, Minnesota, report that secreted frizzled-related protein-4 (sFRP-4), a factor produced by tumors derived from subjects with tumor-induced osteomalacia (TIO, another syndrome associated with excessive renal phosphate excretion), also has phosphaturic activity.In an accompanying commentary on both articles, L. Darryl Quarles from Duke University Medical Center in North Carolina discusses the interactions involved in the coordination of bone mineralization and phosphate handling by the kidney. It remains to be established whether FGF-23 and sFRP-4 represent two distinct phosphatonins or are somehow integrated in a novel phosphate-regulating bone-kidney axis. Quarles suggest that "a bone-kidney hormonal axis would provide a mechanism for the skeleton to communicate with the kidney to coordinate the mineralization of extracellular matrix with the renal handling of phosphate".
TITLE: FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting
AUTHOR CONTACT:
Paolo Bianco
Dipartmento di medicina Sperimentale e Patologia, Universit� "La Sapienza", Rome, Italy
Phone: 39-06-444-1049
Fax: 39-06-494-0896
E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/18399.pdf
ASSOCIATED ARTICLE: TITLE: Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent
AUTHOR CONTACT:
Rajiv Kumar
Mayo Clinic and Foundation, Rochester, Minnesota, USA
Phone: 507-284-0020
Fax: 507-266-4710
E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/18563.pdf
COMMENTARY ACCOMPANYING BOTH ARTICLES:
Evidence for a bone-kidney axis regulating phosphate homeostasis
AUTHOR CONTACT:
L. Darryl Quarles
Duke University Medical Center, Durham, North Carolina, USA
Phone: 919-660-6853
Fax: 919-684-4476
E-mail: [email protected]
View the PDF of this commentary at: https://www.the-jci.org/press/19687.pdf
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Lymphotoxin comes out of the LIGHT in multiple sclerosis
There is a long-standing conflict regarding the role of the lymphotoxin (LT) pathway in multiple sclerosis (MS). By using different animal models, Jen Gommerman and colleagues from Biogen Inc., in Cambridge, Massachusetts, demonstrate a clear role for this pathway in MS. The authors used a fusion protein decoy, which blocks the LT pathway in vivo without evoking the developmental defects inherent in LT-deficient mice. Inhibition of the LT pathway prevented disease in two models of MS. Disease attenuation was due to inhibition of LT and not the related ligand LIGHT. These results suggest that the LT pathway and its ability to maintain lymphoid microenvironments are critical for sustaining late-phase T cell responses in MS. Inhibition of this pathway may be a promising strategy for the treatment of MS as well as other autoimmune diseases.
TITLE: A role for surface lymphotoxin in experimental autoimmune encephalomyelitis independent of LIGHT
AUTHOR CONTACT:
Jennifer Gommerman
University of Toronto, Toronto, Ontario, Canada
Phone: 416-978-6959
Fax: 416-978-1938
E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/18648.pdf
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Steady your nerves, steady your bowels
A study by Matti Airaksinen and colleagues at the University of Helsinki in Finland has provided insight into intestinal obstruction associated with Hirschsprung disease, often suffered by individuals with Down Syndrome. The obstruction is caused by the absence of nerves in a section of intestine, which limits intestinal motility.
Formation of parasympathetic and enteric neurons requires glial cell line�derived neurotrophic factor (GDNF) signaling via GDNF family receptor alpha2 (GFRalpha2). The authors examined the factors that could contribute to growth retardation in GFRA2�/� mice. GFRA knockout mice had fewer intrapancreatic neurons, severely impaired cholinergic innervation of exocrine tissue, and little vagally-mediated stimulation of pancreatic secretion. Knockout mice had retarded growth that could be partially overcome with wet-mash feeding. These results suggest that the growth retardation of the Gfra2�/� mice is largely due to impaired salivary and pancreatic secretion and intestinal dysmotility.
TITLE: Alimentary tract innervation deficits and dysfunction in mice lacking GDNF family receptor alpha2
AUTHOR CONTACT:
Matti Airaksinen
Institute of Biotechnology, University of Helsinki, Helsinki, Finland
Phone: 3589-191-59397
Fax: 3589-191-59560
E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/17995.pdf
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Troponin T controls energetic affairs of the heart
It has long been noted that while patients with familial hypertrophic cardiomyopathy due to cardiac troponin T (cTnT) mutations often suffer sudden cardiac death, they do not develop significant ventricular hypertrophy (ventricle enlargement), suggesting that a distinct cellular mechanism apart from alterations in myocardial contractility is responsible. A new study by Jil Tardiff and colleagues at the Albert Einstein College of Medicine in New York has revealed that a single missense mutation in cTnT causes a striking disruption to energy metabolism, and cardiomyopathy.
In an accompanying commentary, Ketty Schwartz and Jean-Jacques Mercadier from INSERM in Paris discuss how troponin T regulates cardiac contraction and the functional consequences of this mutation.
TITLE: Decreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T
AUTHOR CONTACT:
Jil C. Tardiff
Albert Einstein College of Medicine, Bronx, New York, USA
Phone: 718-430-8914
Fax: 718-430-8989
E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/15967.pdf
ACCOMPANYING COMMENTARY:
Cardiac troponin T and familial hypertrophic cardiomyopathy: an energetic affair
AUTHOR CONTACT: Ketty Schwartz
INSERM U582, Institut F�d�ratif de Recherches 14, Paris, France
Phone: 33-1-42-16-57-05
Fax: 33-1-42-46-57-00
E-mail: [email protected]
View the PDF of this commentary at: https://www.the-jci.org/press/19632.pdf
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Follicular development in the ovary is driven by angiogenesis
Follicles in the ovary require new blood vessel growth in order to develop. The newly formed ovarian blood vessels secure an increasing supply of gonadotropins, growth factors, oxygen, and steroid precursors to the growing follicle. Blockage of angiogenesis can inhibit follicle development partly by blocking hormonal feedback loops between the ovary and the pituitary gland. Ralf Zimmermann and colleagues from Columbia University in New York studied the intraovarian role of VEGFR- 2 activity on follicular development by using a model in which the pituitary gland is absent, the prepuberally hypophysectomized mouse. Hypophysectomy prevents advanced follicle growth and maturation, but follicle development to the preovulatory stage could be stimulated with gonadotropins. The exogenous gonadotropins were unable to drive follicle development to the preovulatory stage in the presence of anti�VEGFR-2 antibodies. These results show that the intraovarian VEGF/VEGFR-2 pathway is critical for gonadotropin-dependent angiogenesis and follicular development.
TITLE: Vascular endothelial growth factor receptor 2�mediated angiogenesis is essential for gonadotropin-dependent follicle development
AUTHOR CONTACT:
Ralf C. Zimmerman
Columbia University College of Physicians and Surgeons, New York, New York, USA
Phone: 212-305-8693
Fax: 212-305-3869
E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/18740.pdf