A bone of contention in drug-induced osteomalacia
Long-term therapy with some antiepileptic drugs and antibiotics can cause osteomalacia, a condition marked by softening of the bones that is usually the result of vitamin D and calcium deficiency. However, the molecular mechanism of drug-induced osteomalacia remains unclear. In a study appearing online on May 11 in advance of print publication in the June issue of the Journal of Clinical Investigation, Kenneth Thummel and colleagues from the University of Washington report that the adverse effect on bone mineral density of these drugs occurs through their activation of the steroid and xenobiotic receptor (SXR), which induces expression of the enzyme CYP3A4 that breaks down vitamin D, diminishing its beneficial effects on bone, and resulting in osteomalacia.
The biologically active forms of vitamin D are broken down to biologically inactive products by the enzyme CYP24, which itself is regulated by the vitamin D receptor (VDR). A 2005 study by another research group that also appeared in the JCI reported that activation of SXR induced CYP24 expression in mice, which would explain an increase in vitamin D breakdown and the resulting osteomalacia observed in individuals taking some SXR-activating antiepileptic drugs or antibiotics. In contrast, the current study by Thummel et al. found that SXR does not induce CYP24 expression in mice to any appreciable extent. Instead, SXR inhibited VDR-mediated CYP24 activity. They also found that treatment of humans with the SXR-activating antibiotic rifampicin had no effect on CYP24 expression, but did increase expression of another enzyme that breaks down vitamin D – CYP3A4. The authors conclude that while SXR negatively regulates CYP24 expression and subsequent vitamin D breakdown, it can also enhance vitamin D hydroxylation and breakdown by inducing the expression of CYP3A4. This explains how SXR activators can cause osteomalacia. The study establishes SXR as a potential therapeutic target for clinical treatment or prevention of osteomalacia.
TITLE: Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia
AUTHOR CONTACT:
Kenneth E. Thummel
University of Washington, Seattle, Washington, USA.
Phone: (206) 543-0819; Fax: (206) 543-3204; E-mail: thummel@u-washington.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27793
VIROLOGY
IL-15 therapy restores T cell production in an animal model of HIV infection
The preferred targets of the HIV virus are effector memory T cells that constitute the CD4+ T cell population in extralymphoid sites like the intestine, lung, and vaginal mucosa. HIV infection causes massive depletion of this cell population and their regeneration is inefficient, even in individuals receiving antiretroviral therapy (ART). Therefore, restoration of this depleted cell population has long been a therapeutic goal in HIV infection. In a study appearing online on May 11 in advance of print publication in the June issue of the Journal of Clinical Investigation, Louis Picker and colleagues from Oregon Health & Science University examined an animal model of HIV infection [simian immunodeficiency virus (SIV) infection in rhesus macaques] receiving ART and show that IL-15 administration dramatically increased the number of CD4+ and CD8+ effector memory T cells and these cells rapidly disperse to extralymphoid sites. The results of this study suggest that the use of IL-15 in HIV+ individuals with effective viral suppression due to antiretroviral therapy might facilitate specific restoration of the CD4+T cell population.
TITLE: IL-15 induces CD4+ effector memory T cell production and tissue emigration in nonhuman primates
AUTHOR CONTACT:
Louis J. Picker
Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA.
Phone: (503) 418-2720; Fax: (503) 418-2719; E-mail: pickerl@ohsu.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27564
NEUROBIOLOGY
Mechanism of lithium action for the treatment of bipolar disorder
Calcium is a common intracellular signaling molecule with a wide range of functions in the brain, and the regulation as well as dysregulation of calcium signaling via the principal intracellular calcium release channel, InsP3R1, has been linked to many normal cellular processes as well as neurological diseases. In addition, the calcium binding protein, neuronal calcium sensor-1 (NCS-1), has been shown to regulate calcium signaling and NCS-1 expression is increased in bipolar patients. In a study appearing online on May 11 in advance of print publication in the June issue of the Journal of Clinical Investigation, Barbara E. Erhlich and colleagues from Yale University set out to determine if NCS-1 and InsP3R1 interact with each and if this interaction was altered in neuropathological disorders. They found that, in intact rat cells, NCS-1 dramatically increased the rate at which the InsP3R channel opened and released calcium, which would result in enhanced calcium signals at synapses in the brain. As lithium was introduced over a half-century ago for the treatment of the alternating occurrence of mania and depression that is characteristic of bipolar disorder, the authors tested the effect of lithium on the interaction between NCS-1 and InsP3R1. Therapeutic levels of lithium were found to block the effect of NCS-1 on InsP3R1 function, suggesting that the InsP3R1/NCS-1 interaction is an essential part of the mechanism of bipolar disorder. The study reveals the role of NCS-1 and suggests that it is a promising target for the treatment of neuropsychiatric disorders.
TITLE: Neuronal calcium sensor-1 enhancement of InsP3 receptor activity is inhibited by therapeutic levels of lithium
AUTHOR CONTACT:
Barbara E. Ehrlich
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: (203) 737-1158; Fax: (203) 737-2027; E-mail: barbara.ehrlich@yale.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=22466
METABOLIC DISEASE
MCP-1: the missing link between obesity and insulin resistance
Individuals diagnosed with metabolic syndrome often have excessive fatty tissue in and around their abdomen, high cholesterol, elevated blood pressure, and an inability to utilize insulin or blood sugar (insulin resistance) – symptoms that put them at high risk of coronary heart disease and stroke. The molecular mechanisms that link obesity and insulin resistance are the subject of intense investigation and are not completely understood.
In a study appearing online on May 11 in advance of print publication in the June issue of the Journal of Clinical Investigation, Yoshikazu Tamori and colleagues from Kobe University, Japan, show that the concentration of monocyte chemoattractant protein-1 (MCP-1) in fat cells and blood plasma was increased both in genetically obese diabetic mice as well as healthy mice in which obesity had been induced by feeding them a high-fat diet. Mice expressing an MCP-1 transgene in fat cells exhibited insulin resistance, increased infiltration of macrophages into fatty tissue, and high cholesterol levels. In addition, these effects were not observed in mice lacking MCP-1 even when fed the high-fed diet. The results of this study suggest that MCP-1 links obesity and insulin resistance by the induction of an inflammatory response (macrophage infiltration) in fatty tissue. The authors suggest that blocking the interaction of MCP-1 and its receptor, known as CCR2, might provide the basis for development of new therapies for this syndrome.
TITLE: MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity
AUTHOR CONTACT:
Yoshikazu Tamori
Kobe University, Kobe, Japan.
Phone: 81-78-382-5861; Fax: 81-78-382-2080; E-mail: tamori@med.kobe-u.ac.jp
View the PDF of this article at: https://www.the-jci.org/article.php?id=26498
PHYSIOLOGY
Dysfunctional Cyp4a10 enzyme causes dietary salt–sensitive increases in blood pressure
Both the volume of water and salt content of the body can affect blood pressure. The kidneys act to filter the blood and rid our bodies of excess salt or water and in doing so play a central role in the maintenance of normal blood pressure. In a study appearing online on May 11 in advance of print publication in the June issue of the Journal of Clinical Investigation, Jorge Capdevila and colleagues from Vanderbilt University show that a dysfunctional Cyp4a10 gene causes a type of high blood pressure in mice that is, like most high blood pressure in humans, sensitive to dietary salt intake. They show that Cyp4a10-/- mice had normal blood pressure when fed a normal diet, yet developed high blood pressure when fed a high-salt diet. These mice had a dysfunctional sodium channel in kidney epithelial cells, which caused alterations in the passage of sodium in and out of kidney cells, thereby upsetting the ability of the kidneys to regulate sodium excretion and blood pressure. These results could lead to new strategies for the early diagnosis and clinical management of salt-sensitive high blood pressure.
TITLE: Salt-sensitive hypertension is associated with dysfunctional Cyp4a10 gene an kidney epithelial sodium channel
AUTHOR CONTACT:
Jorge H. Capdevila
Vanderbilt University, Nashville, Tennessee, USA.
Phone: (615) 322-4968; Fax: (615) 343-4704; E-mail: jorge.capdevila@vanderbilt.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27546
Journal
Journal of Clinical Investigation