Osteoporosis is prevalent in postmenopausal women. The underlying reason is mainly estrogen deficiency, but recent studies have indicated that osteoporosis is also associated with iron accumulation after menopause. It has been confirmed that some methods of decreasing iron accumulation can improve the abnormal bone metabolism associated with postmenopausal osteoporosis. However, the mechanism of iron accumulation-induced osteoporosis is still unclear. Iron accumulation may inhibit the canonical Wnt/β-catenin pathway via oxidative stress, leading to osteoporosis by decreasing bone formation and increasing bone resorption via the osteoprotegerin (OPG)/receptor activator of nuclear factor kappa-B ligand (RANKL)/receptor activator of nuclear factor kappa-B (RANK) system. In addition to oxidative stress, iron accumulation also has been reported to inhibit either osteoblastogenesis or osteoblastic function as well as to stimulate either osteoclastogenesis or osteoclastic function directly. Furthermore, serum ferritin has been widely used for the prediction of bone status, and nontraumatic measurement of iron content by magnetic resonance imaging may be a promising early indicator of postmenopausal osteoporosis.

TRACE-METAL CONTROL OF SPECIFIC BIOSYNTHETIC PROCESSES EUGENE D. WEINBERG* . . . there probably does not exist a single enzyme-catalyzed reaction in which either substrate , product, enzyme, or some combination within this triad is not influenced in a very direct and highly specific manner by the precise nature ofthe inorganic ions which surround and "modify" it.—H. R. Mahler (i). I. Introduction During the past quarter-century it has become increasingly apparent that, for efficient metabolism and growth, living matter must be supplied a proper balance ofbiologically available trace metals (2-4). A corollary to this observation has been sometimes recognized: namely, that a specific distortion of normal metabolism often can be achieved by appropriate alteration ofthe balance ofavailable trace metals. Recognition and utilization of this corollary has occurred unevenly in the various basic and applied areas ofbiology; at present, however, a considerable number ofabnormal or diseased metabolic states ofmicrobes, plants, animals, and man are known to be associated with imbalances of trace metals in either the diet or in specific tissues (2-7). Moreover, the selective biological activities ofvitamins, hormones, and drugs are, in numerous instances, believed to be closely associated with and even dependent upon the presence ofspecific trace metals (2, 8-15). The purpose ofthis essay is to direct attention to the pervasiveness of trace-metal control ofspecific biosynthetic processes in fully grown tissues or in mature cell cultures. The studies to be cited are generally restricted to those in which a comparison was made ofthe balance oftrace metals re- * Department ofBacteriology, Indiana University, Bloomington, Indiana. Research for this paper was supported by grant E-4184 from the National Institute of Allergy and Infectious Diseases, U.S.P.H.S. Portions were written during theauthor s appointmentas a Visiting Scientist at Commercial Solvents Corporation, Terre Haute, Indiana. 432 Eugene D. Weinberg · Trace-Metal Control Perspectives in Biology and Medicine · Summer 1962 quired for normal growth and metabolism with the balance required for a specific metabolic distortion. Emphasis will be placed on demonstrations that slight shifts in the kind and quantity ofavailable trace metals required for optimum growth ofa given living system strongly promoted or suppressed the biosynthesis ofa specific metabolite by either the growing or the mature system. In the majority of cases to be described, the shifts had little effect on the rate or extent ofgrowth. The most practical living systems for this type ofstudy are, ofcourse, homogeneous cell cultures. As might be expected because oftheir commercial importance, a good deal of information has been amassed for bacterial and mycotic cell cultures. In contrast, very few such studies have been performed on plant or animal cell cultures, and it is hoped that this paperwillstimulatetheinitiationofsuchprojects.Insomeofthestudiestobe cited, it will be noted that observations were made ofan entire physiological process such as cell differentiation rather than ofthe synthesis ofa specific compound. Such physiological processes are presumably the end result ofthe synthesis ofa "triggering" compound(s); possibly this synthesis is altered by the shift in trace-metal balance described. Alternately, the shift in trace metals may affect a subsequent metabolic step that can cause the process either to abort or to go on to completion. II. Examples of Trace-Metal Control Table ? contains a partial list ofexamples oftrace-metal control ofbiosynthetic processes. As may be noted in columns ? and 2, the synthesis or execution ofa wide variety of metabolites or physiological processes by plant, microbial, and animalcells can be influenced by the presence of one or a few trace metals in concentrations that differ from those required for optimal growth. As might be expected, the kinds ofmetals (columns 3a and 36) that were active in the various systems are usually those that can be activators ofspecific enzymes (1, 3); other metals were either completely inert or else were nonspecific poisons of the entire enzymatic content of the living systems. In nearly all the examples cited in the table, various biologically active trace metals were tested. As may be seen in columns 3

During the past fifteen years, awareness of iron associated complications of pregnancy has markedly increased [1-8]. Although 97.5% of U.S. pre-menopausal women are reported to be iron replete [9], some gravid women, to overcome fatigue, consume over-thecounter iron supplements. Complications associated with elevated iron during pregnancy include increased retinopathy of prematurity [2], teratogenicity [4], gestational diabetes [5], preeclampsia [6], and GRACILE syndrome [7]. Thus it would be prudent to advise pregnant persons, in the absence of determination of actual iron deficiency, to avoid excessive iron.

Copyright: © 2014 Weinberg ED. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. During the past five decades, scores of medical studies have described the association of ferrotoxicity with development of a great variety of diseases [1]. Increasingly, specific types of body cells are being reported to be injured or killed by low concentrations of iron. In the initial account, cultures of anterior pituitary cells were observed to be killed by 2 μM irons; in this system, hepatocytes remained healthy in 10-100 μM iron [2]. Thus not surprisingly, thalassemic-major children who load iron early in life are deprived of growth hormone. Persons who absorb excessive iron in late teens or early adulthood can suffer from low levels of gonadotrophic hormones. Subsequently, osteoblasts have been recognized to be unusually sensitive to low concentrations of iron [3,4]. In contrast, osteoclasts (cells of macrophage origin) are highly resistant to iron. Thus in iron loaded persons, bone rebuilding by osteoblasts is surpassed by osteoclast destruction of bone. Accordingly, osteoporosis is a common disorder in patients who load iron for genetic, environmental or behavioral reasons [5].

Increasingly, we are becoming aware that excessive/misplaced iron is a notable risk factor for a broad spectrum of diseases [1]. Moreover, the mechanisms of ferrotoxicity differ significantly among specific diseases. Infectious diseases and cancers Iron is dangerous because it is an essential growth factor for most bacterial, all fungal and all protozoan infections [2] as well as for all cancer cells [3]. Although viruses do not have independent metabolism, enhanced host iron is needed for viral synthesis [2]. Our bodies employ a constitutive iron withholding defense system that strives to prevent invader access to the metal. Moreover, the system is promptly and markedly upregulated at the time of threatened microbial and viral infections and cancer cell invasions [4]. Chronic diseases Iron is dangerous because of its oxidative potential for highly sensitive key cells that are specific for the disease. Examples of the key cells include: (1) anterior pituitary cells that stimulate endocrine gland activities [5], (2) osteoblasts that rebuild bone [6] and (3) pancreatic beta cells that produce insulin [7]. These cells are killed by concentrations of iron that are several orders of magnitude lower than lethal quantities of iron for hepatocytes, macrophages, osteoclasts and pancreatic exocrine cells. Thus it can be predicted that, in other chronic diseases, key body cells for relevant organ functions likewise will be found to be unusually sensitive to iron killing. A prime nominee is the ventricular cardiomyocyte, essential for heart health [8]. Conclusion Excessive/misplaced iron, a ubiquitous component of disease causation, is dangerous in two ways. For infections and cancers, the metal is essential for invader growth. For chronic maladies, the metal is exceptionally lethal for key cells that are required for specific organ functions.

TNF-α is a central regulator of inflammation and its blockade downregulates other pro-inflammatory cytokines, chemokines, and growth factors. Subsequently, TNF-α antagonists are currently used in treatment regimens directed toward several inflammatory diseases. Despite a beneficial effect, the use of TNF-α antagonists is associated with an increased risk for infections and neoplasms; the basis for these complications is unclear. This cytokine also participates in iron homeostasis and the sequestration of this metal, mediated by TNF-α, is considered protective. We hypothesize that treatment with TNF-α antagonists predisposes the patient to infections and neoplasms by reversing the sequestration of host iron mediated by the cytokine and increasing available concentrations of this metal. It is recommended that patients who are to receive TNF-α antagonists be tested for iron overload and the use of these agents in those individuals with excess iron should be reconsidered. Furthermore, it is predicted that alternative attempts to treat inflammatory diseases by blocking other pivotal cytokines that also participate in iron homeostasis (e.g. IFN-γ, IL-1, and IL-6) will similarly be associated with infections and neoplastic complications.

Iron overload cardiomyopathy is becoming more prevalent, and early recognition and intervention may alter outcomes. Calcium channels are key transporters of iron under iron-overloaded conditions, and potentially represent a new therapeutic target for iron overload. The purpose of this study was to examine the relationship between Calcium channel blocker (CCB) use and serum ferritin among adults with diagnosed hypertension. We analyzed the nationally representative NHANES (National Health and Nutrition Examination Survey) 1999–2002 for adults ≥40 years with diagnosed hypertension. The association between CCBs and serum ferritin was assessed using a t-test and adjusted multiple regressions.The study population included 2143 individuals (representing 37.4 million individuals, 42.0 % males). 12.6 % of the population reported taking CCBs in the last month. Individuals taking CCBs had lower mean serum ferritin (129.3 ng/mL versus 154.5 ng/mL, p = 0.02). After adjusting for age, sex, menopause and hysterectomy status for women, race/ethnicity, and C-reactive protein, mean serum ferritin for individuals taking CCBs was 26.3 ng/mL lower than for those not taking CCBs (p = 0.01). In an adjusted regression, individuals who took CCBs and had a daily vitamin C intake of ≥500 mg had a mean serum ferritin that was 60.1 ng/mL lower than people not taking CCBs and with daily vitamin C < 500 mg (p < 0.001). In conclusion, this study found an association between use of CCBs and lower serum ferritin levels in individuals with hypertension. Further studies are needed to assess the possible use of CCBs as non-traditional chelating agents for treatment of iron overload cardiomyopathy.

Excessive or misplaced tissue iron now is recognized to pose a substantial health risk for an extensive array of endocrinological, gastrointestinal, infectious, neoplasmic, neurodegenerative, obstetric, ophthalmic, orthopedic, pulmonary and vascular diseases. Ingested, injected, inhaled and decompartmentalized iron contributes not only to disease, but also to aging and mortality. Iron is dangerous by catalyzing free radical formation and by serving as an essential nutrient for microbial and neoplasmic cell invaders. Our body cells exhibit wide variation in sensitivity to iron toxicity. Efficacy of our iron withholding defense system is modulated by numerous environmental, behavioral and genetic factors. A notable variety of methods for prevention and therapy of iron toxicity are now becoming available.

Several kinds of evidence indicate that elevated iron during the 3-8 week embryonic (organogenesis) period of human gestation may be teratogenic. (1) In the embryonic period, the natural maternal absorption of food iron is 30% below the estimated daily iron loss. (2) As compared with maternal serum, embryonic fetal coelomic fluid contains only one-fourth as much iron but nearly six times the quantity of the iron withholding protein, ferritin. (3) In the embryonic period, intraplacental oxygen pressure is 2-3 times lower than in the subsequent fetal growth period. (4) Iron is a strong inducer of emesis which peaks in the embryonic period. (5) In a murine gestation model, iron was neurotoxic at a sharp peak of 8-9 days. Thus it would be prudent, in human pregnancy, to delay any needed iron supplementation until the embryonic period has been completed.

During the past half century, excessive/misplaced iron has been observed to be a risk factor for an increasing number and diversity of disease conditions. An extensive list of conditions and of the types of iron association were published in early 2008. Within the subsequent year, four additional disorders have been recognized to be enhanced by iron: aging muscle atrophy, viral replication, rosacea and pulmonary alveolar proteinosis. This paper adds new data and emphasis on these disorders as entities associated with increased iron load and toxicity.

The great majority of US adults are iron replete; indeed, some are burdened with an excessive amount of the metal. Nevertheless, iron continues to be added by food processors to such items as flour, other grains and ready-to-eat cereals. In some cases, actual added quantities exceed the labeled amounts. Iron is a dangerous pro-oxidant as well as a mutagen and carcinogen. The metal is a serious risk factor for a variety of cardiovascular, endocrine, infectious, neoplasmic, neurodegenerative, orthopedic and respiratory diseases. For many of the conditions, iron can be a sole initiator or a cofactor in promoting the disease. For others, iron deposits are found in relevant tissue sites. For numerous additional diseases, iron is associated with elevated disease incidence. Accordingly, critical evaluation of the indiscriminate practice of adding the metal to processed foods is overdue.

To cause infection, nearly all protozoa, fungi, and bacteria must obtain growth-essential iron from their hosts. To suppress infection, hosts have evolved iron-withholding defense systems. Enhancement of iron withholding is a potential target for the development of novel therapeutic agents. This review focuses on the association of iron with current and emerging antimalarial drugs. Proposed mechanisms of antimalarial action of (1) iron-requiring agents, the artemisinins, are compared with (2) a spectrum of compounds that withdraw iron by chelation. A novel approach to malarial chemotherapy might involve the sequential use of a member of each of the two categories.

In human pregnancies, maternal absorption of iron is markedly curtailed in the first trimester. In a murine model, iron was teratogenic in the analogous embryonic period. Although iron is a weak mutagen, it is a powerful oxidant and a catalyst of formation of hydroxyl radicals. Studies are needed to determine if there might be an association of first trimester iron supplementation with miscarriage/fetal abnormalities.

Iron replete pregnant women often are routinely advised to take a daily supplement of 30–40mg iron. An extensive review of controlled trials has failed to demonstrate that this practice improves clinical outcome of mother or newborn. However, this iron loading has long been assumed to be harmless. Recently, two hazardous complications of pregnancy, gestational diabetes and pre-eclampsia, have been recognized to be associated with iron loading. Accordingly, it may be appropriate to consider performing, at the patient’s initial prenatal medical visit, a serum ferritin test to ascertain iron status. This simple procedure would enable evidence-based medical practice to replace mass medication with iron, a potentially toxic element.

Background: To successfully sustain an infection, nearly all bacteria, fungi and protozoa require a continuous supply of host iron.Methods: Literature review.Results: Mechanisms of microbial iron acquisition are determinants for the kinds of cells, tissues and hosts in which pathogens can flourish. As a corollary, hosts possess an array of iron withholding devices whereby they can suppress or abort microbial invasions.General significance: Awareness of environmental and behavioral methods that can prevent iron loading plus development of pharmaceutical agents that can block microbial access to iron may help to reduce our dependence on antibiotics. (C) 2008 Elsevier B.V. All rights reserved.

Osteoporosis is a remarkably frequent complication of iron loading conditions such as thalassemia, sicklemia, African siderosis, hemochromatosis, smoking, alcoholism, HIV infection, and cessation of menstruation. The metal suppresses osteoblast formation of bone and may also stimulate osteoclast resorption of bone. Iron also inhibits anterior pituitary synthesis of gonadotrophs. This, in turn, results in depressed formation of gonadal hormones. The tendency of iron-loaded persons to become osteoporotic may be enhanced by gonadal hormone deficiency. Iron binding agents that could specifically withhold excess skeletal iron (and be excreted as the iron chelate) might have therapeutic utility.