Jerry L. Pettis Memorial VA Medical Center

I. Introduction II. Characteristics of the IGFBPs III. Target Cell Actions of the IGFBPs A. To modulate IGF actions B. To facilitate storage of IGFs in extracellular matrices C. To exert IGF

IGF-I is expressed in virtually every tissue of the body, but with much higher expression in the liver than in any other tissue. Studies using mice with liver-specific IGF-I knockout have demonstrated that liver-derived IGF-I, constituting a major part of circulating IGF-I, is an important endocrine factor involved in a variety of physiological and pathological processes. Detailed studies comparing the impact of liver-derived IGF-I and local bonederived IGF-I demonstrate that both sources of IGF-I can stimulate longitudinal bone growth. We propose here that liver-derived circulating IGF-I and local bone-derived IGF-I to some extent have overlapping growth-promoting effects and might have the capacity to replace each other ( redundancy) in the maintenance of normal longitudinal bone growth. Importantly, and in contrast to the regulation of longitudinal bone growth, locally derived IGF-I cannot replace ( lack of redundancy) liver-derived IGF-I for the regulation of a large number of other parameters including GH secretion, cortical bone mass, kidney size, prostate size, peripheral vascular resistance, spatial memory, sodium retention, insulin sensitivity, liver size, sexually dimorphic liver functions, and progression of some tumors. It is clear that a major role of liver-derived IGF-I is to regulate GH secretion and that some, but not all, of the phenotypes in the liver-specific IGF-I knockout mice are indirect, mediated via the elevated GH levels. All of the described multiple endocrine effects of liver-derived IGF-I should be considered in the development of possible novel treatment strategies aimed at increasing or reducing endocrine IGF-I activity. (Endocrine Reviews 30: 494 -535, 2009) I. Introduction II. Liver-Derived IGF-I and Longitudinal Bone Growth A. Background, including the original somatomedin hypothesis B. Tissue-specific manipulation of IGF-I expression C. Target cells for GH and IGF-I in the growth plate D. Human genetic disorders and skeletal growth E. Mechanism of action for GH and IGF-I in the regulation of bone growth-an update III. Effects of Liver-Derived vs. Locally Produced IGF-I on Bone Mass A. In vivo and in vitro studies on IGF-I expression and action in bone B. Transgenic overexpression in bone C. Conditional knockout in bone D. Liver-derived IGF-I and bone mass IV. Liver-Derived IGF-I and GH Secretion A. Pulsatile GH secretion B. Negative feedback of liver-derived IGF-I on GH secretion C. Liver-derived IGF-I and sexually dimorphic effects of GH D. Human studies V. The Role of Liver-Derived IGF-I for Metabolism and Body Composition A. Carbohydrate metabolism B. Fat mass C. Lipid metabolism VI. Liver-Derived IGF-I and Other Tissues A. Brain B. Cardiovascular system C. Kidney D. Liver E. Prostate VII. Clinical Implications A. Indications for the use of IGF-I and adverse effects B. Potential indications for combined GH and IGF-I treatment C. Diabetes mellitus D. Other potential future indications

Life on earth has evolved in a sea of natural electromagnetic (EM) fields. Over the past century, this natural environment has sharply changed with introduction of a vast and growing spectrum of man-made EM fields. From models based on equilibrium thermodynamics and thermal effects, these fields were initially considered too weak to interact with biomolecular systems, and thus incapable of influencing physiological functions. Laboratory studies have tested a spectrum of EM fields for bioeffects at cell and molecular levels, focusing on exposures at athermal levels. A clear emergent conclusion is that many observed interactions are not based on tissue heating. Modulation of cell surface chemical events by weak EM fields indicates a major amplification of initial weak triggers associated with binding of hormones, antibodies, and neurotransmitters to their specific binding sites. Calcium ions play a key role in this amplification. These studies support new concepts of communication between cells across the barriers of cell membranes; and point with increasing certainty to an essential physical organization in living matter, at a far finer level than the structural and functional image defined in the chemistry of molecules. New collaborations between physical and biological scientists define common goals, seeking solutions to the physical nature of matter through a strong focus on biological matter. The evidence indicates mediation by highly nonlinear, nonequilibrium processes at critical steps in signal coupling across cell membranes. There is increasing evidence that these events relate to quantum states and resonant responses in biomolecular systems, and not to equilibrium thermodynamics associated with thermal energy exchanges and tissue heating.

Traditionally, binding proteins are known to regulate the activity of ligands by prolonging their half-life, and insulin-like growth factor (IGF)-binding proteins (IGFBPs) are no exception to this. The IGFBP family contains six high-affinity members with variable functions and mechanisms of actions. In addition to functioning as simple carrier proteins, IGFBPs in serum function to regulate the endocrine actions of IGFs by regulating the amount of IGF available to bind to signaling IGF-I receptors, whereas locally produced IGFBPs act as autocrine/paracrine regulators of IGF action. Furthermore, recent in vitro and in vivo findings that IGFBPs function independently of the IGFs as growth modulators are particularly exciting. Regarding the role of IGFBPs as ligand-independent growth modulators, our recent data that IGFBP-5 stimulates markers of bone formation in osteoblasts lacking functional IGFs provide evidence that IGFBP-5 itself is a growth factor that can act independently of IGFs to regulate bone formation. In terms of the mechanism by which certain IGFBPs mediate their effects in a ligand-independent manner, the binding of IGFBP to its putative receptor on the cell membrane may stimulate the signaling pathway independent of an IGF receptor, to mediate the effects of IGFBPs in certain target cell types. IGFBPs may also exert IGF-independent effects by transcriptional activation of genes by IGFBPs transported into the nucleus via their nuclear localization signal. In conclusion, IGFBPs are unusually pleotrophic molecules with functions ranging from the traditional role of prolonging the half-life of the IGFs to functioning as growth factors independent of the IGFs. In this regard, it was surprising to find that the human genome contains only about 35 000 genes. One mechanism to account for such complexity with a relatively small number of genes is strikingly illustrated by the multifunctional IGFBP class of proteins.

Androgens may regulate the male skeleton directly through a stimulation of androgen receptors or indirectly through aromatization of androgens into estrogen and, thereafter, through stimulation of estrogen receptors (ERs). The relative importance of ER subtypes in the regulation of the male skeleton was studied in ERalpha-knockout (ERKO), ERbeta-knockout (BERKO), and double ERalpha/beta-knockout (DERKO) mice. ERKO and DERKO, but not BERKO, demonstrated decreased longitudinal as well as radial skeletal growth associated with decreased serum levels of insulin-like growth factor I. Therefore, ERalpha, but not ERbeta, mediates important effects of estrogen in the skeleton of male mice during growth and maturation.

BACKGROUND: Gap junctions are thought to have a crucial role in the synchronized contraction of the heart and in embryonic development. Connexin43, the major protein of gap junctions in the heart, is targeted by several protein kinases that regulate myocardial cell-cell coupling. We hypothesized that mutations altering sites critical to this regulation would lead to functional or developmental abnormalities of the heart. METHODS: Connexin43 DNA from 25 normal subjects and 30 children with a variety of congenital heart diseases was amplified by the polymerase chain reaction and sequenced. Mutant DNA was expressed in cell culture and examined for its effect on the regulation of cell-cell communication. RESULTS: The 25 normal subjects and 23 of the 30 children with heart disease had no amino acid substitutions in connexin43. All six children with syndromes that included complex heart malformations had substitutions of one or more phosphorylatable serine or threonine residues. Four of these children had two independent mutations, suggesting an autosomal recessive disorder. Five of these children had substitutions of proline for serine at position 364. A seventh child, with a different heart condition, also had a point mutation in connexin43. Transfected cells expressing the Ser364Pro mutant connexin43 sequence showed abnormalities in the regulation of cell-cell communication, as compared with cells expressing normal connexin43. CONCLUSIONS: Mutations in the connexin43 gap-junction gene, which lead to abnormally regulated cell-cell communication, are associated with visceroatrial heterotaxia.

Eleven young adult subjects were briefly awakened after each minute of electroencephalographic-defined sleep for 2 consecutive nights after undisturbed laboratory adaptation and baseline nights. Two undisturbed recovery nights followed disruption nights. On disruption nights, subjects were awakened with an audiometer and signaled the awakening by subjective rating of sleep state or button push response. The disruption procedure resulted in severely fragmented sleep with only very small amounts of slow-wave and REM sleep. Total sleep time was reduced by approximately 1 h on each night. Arousal threshold increased 56 dB across the disruption nights. Following disruption, subjects performed more poorly and rated themselves sleepier than on baseline. The level of decline was similar to that seen after periods of total sleep loss of 40-64 h. Recovery sleep was also similar to that seen after total sleep loss. It was concluded that periodic disruption of sleep, perhaps by destroying sleep continuity, quickly results in impaired function. These data may help explain function loss in severe sleep apneics.

Indoleamine 2, 3-dioxygenase (IDO) is the first and rate limiting catabolic enzyme in the degradation pathway of the essential amino acid tryptophan. By cleaving the aromatic indole ring of tryptophan, IDO initiates the production of a variety of tryptophan degradation products called "kynurenines" that are known to exert important immuno-regulatory functions. Because tryptophan must be supplied in the diet, regulation of tryptophan catabolism may exert profound effects by activating or inhibiting metabolism and immune responses. Important for survival, the regulation of IDO biosynthesis and its activity in cells of the immune system can critically alter their responses to immunological insults, such as infection, autoimmunity and cancer. In this review, we assess how IDO-mediated catabolism of tryptophan can modulate the immune system to arrest inflammation, suppress immunity to cancer and inhibit allergy, autoimmunity and the rejection of transplanted tissues. Finally, we examine how vaccines may enhance immune suppression of autoimmunity through the upregulation of IDO biosynthesis in human dendritic cells.

BODEN, WILLIAM E.; O'ROURKE, ROBERT A.; CRAWFORD, MICHAEL H.; BLAUSTEIN, ALVIN S.; DEEDWANIA, PRAKASH C.; ZOBLE, ROBERT G.; WEXLER, LAURA F.; KLEIGER, ROBERT E.; PEPINE, CARL J.; FERRY, DAVID R.; CHOW, BRUCE K. PHILIP W. LAVORI FOR THE VETERANS AFFAIRS NON-Q-WAVE INFARCTION STRATEGIES IN HOSPITAL (VANQWISH) TRIAL INVESTIGATORS Author Information

Low-energy electromagnetic fields pulsed at frequencies of 10-90 Hz significantly increase healing of chronic fracture nonunions in man. These fields are effective at tissue current levels several orders of magnitude lower than those required for transmembrane depolarization of normal cells. We have examined the effects of two clinically used pulsed electromagnetic fields on cultures of the osteoblast-like mouse bone cell line MMB-1. Both fields significantly reduced cellular production of cAMP in response to parathyroid hormone and osteoclast activating factor. Neither basal nor fluoride-activated levels of adenylate cyclase were altered in membranes from cells cultured in the fields; however, the same membrane preparations exhibited markedly inhibited responses to parathyroid hormone. The fields blocked the inhibitory effects of the hormone on collagen synthesis by MMB-1 cells. However, there was no effect on the inhibition of collagen synthesis by 1,25-dihydroxyvitamin D(3), which is believed to act primarily by a nuclear, rather than by a membrane-dependent, mechanism. No significant differences were noted between effects of the two fields, one generating continuous pulse trains (72 Hz) and the other generating recurrent bursts (15 Hz) of shorter pulses. We hypothesize that these field effects are mediated primarily at the plasma membrane of osteoblasts, either by interference with hormone-receptor interactions or by blocking of receptor-cyclase coupling in the membrane. These responses occurred with induced extracellular fields of 1 mV/cm or less, even though transmembrane potential gradients are typically 10(5) V/cm.

Occult hepatitis B virus (HBV) infection is characterized by presence of HBV infection with undetectable hepatitis B surface antigen (HBsAg). Serum HBV level is usually less than 104 copies/mL in these patients. Diagnosis of occult HBV infection requires sensitive HBV-DNA PCR assay. Several possibilities have been hypothesized as the mechanisms of occult HBV infection. These include: (i) mutations of HBV-DNA sequence; (ii) integration of HBV-DNA into host's chromosomes; (iii) infection of peripheral blood mononuclear cells by HBV; (iv) formation of HBV-containing immune complex; (v) altered host immune response; and (vi) interference of HBV by other viruses. The precise prevalence of occult HBV infection remains to be defined. The clinical implications of occult HBV infection involve different clinical aspects. First of all, occult HBV infection harbours potential risk of HBV transmission through blood transfusion, haemodialysis, and organ transplantation. Second, it may serve as the cause of cryptogenic liver disease, contribute to acute exacerbation of chronic hepatitis B, or even fulminant hepatitis. Third, it is associated with development of hepatocellular carcinoma. Fourth, it may affect disease progression and treatment response of chronic hepatitis C. Most of the previous studies utilized retrospective observation without control groups, and lacked direct association of occult HBV infection with specific pathological changes and disease progression. Highly sensitive, quantitative, and functional molecular analyses of HBV, combined with a well-designed prospective clinical assessment will provide the best approach for the future study of occult HBV infection.

This study evaluated if melatonin would increase bone mass in mice. Four groups of 4-week-old male ddy mice received daily injections of vehicle or 1, 5, or 50 mg/kg of melatonin, respectively, for 4 weeks. Treatment with 5 mg/kg per day or 50 mg/kg per day of melatonin significantly increased bone mineral density (BMD; by 36%, p < 0.005) and bone mass (bone volume per tissue volume [BV/TV] by 49%, p < 0.01, and trabecular thickness [Tb.Th] by 19%, p < 0.05). This treatment significantly reduced bone resorption parameters (i.e., osteoclast surface [Oc.S/bone surface [BS]] by 74%,p < 0.05, and osteoclast number [N.Oc/BS] by 76%,p < 0.005) but did not increase histomorphometric bone formation parameters (i.e., bone formation rate [BFR/ BS], mineral apposition rate [MAR], and osteoid volume [OV/TV]), indicating that melatonin increases bone mass predominantly through suppression of bone resorption. Melatonin (1-500 microM) in vitro caused dose-dependent reduction (p < 0.001 for each) in the number and area of resorption pits formed by osteoclasts derived from bone marrow cells but not those formed by isolated rabbit osteoclasts. Because RANKL increases, while osteoprotegerin (OPG) serves as a soluble decoy receptor for RANKL to inhibit osteoclast formation and activity, the effect of melatonin on the expression of RANKL and OPG in mouse MC3T3-E1 osteoblastic cells was investigated. Melatonin (5-500 microM) increased in a dose-dependent manner and reduced the mRNA level of RANKL and both mRNA and protein levels of OPG in MC3T3-E1 cells (p < 0.001 for each). In summary, these findings indicated for the first time that melatonin at pharmacologic doses in mice causes an inhibition of bone resorption and an increase in bone mass. These skeletal effects probably were caused by the melatonin-mediated down-regulation of the RANKL-mediated osteoclast formation and activation.

Significant differences in vertebral (9%) and femoral (50%) adult bone mineral density (BMD) between the C57BL/6J (B6) and C3H/HeJ (C3H) inbred strains of mice have been subjected to genetic analyses for quantitative trait loci (QTL). Nine hundred eighty-six B6C3F2 females were analyzed to gain insight into the number of genes that regulate peak BMD and their locations. Femurs and lumbar vertebrae were isolated from 4-month-old B6C3F2 females at skeletal maturity and then BMD was determined by peripheral quantitative computed tomography (pQCT). Estimates of BMD heritability were 83% for femurs and 72% for vertebrae. Genomic DNA from F2 progeny was screened for 107 polymerase chain reaction (PCR)-based markers discriminating B6 and C3H alleles on all 19 autosomes. The regression analyses of markers on BMD revealed ten chromosomes (1, 2, 4, 6, 11, 12, 13, 14, 16, and 18) carrying QTLs for femurs and seven chromosomes (1, 4, 7, 9, 11, 14, and 18) carrying QTLs for vertebrae, each with log10 of the odds ratio (LOD) scores of 2.8 or better. The QTLs on chromosomes (Chrs) 2, 6, 12, 13, and 16 were unique to femurs, whereas the QTLs on Chrs 7 and 9 were unique to vertebrae. When the two bone sites had a QTL on the same chromosome, the same marker had the highest, although different, LOD score. A pairwise comparison by analysis of variance (ANOVA) did not reveal significant gene x gene interactions between QTLs for either bone site. BMD variance accounted for by individual QTLs ranged from 1% to 10%. Collectively, the BMD QTLs for femurs accounted for 35.1% and for vertebrae accounted for 23.7 % of the F2 population variances in these bones. When mice were homozygous c3/c3 in the QTL region, 8 of the 10 QTLs increased, while the remaining two QTLs on Chrs 6 and 12 decreased, femoral BMD. Similarly, when mice were homozygous c3/c3 in the QTL region for the vertebrae, five of the seven QTLs increased, while two QTLs on Chrs 7 and 9 decreased, BMD. These findings show the genetic complexity of BMD with multiple genes participating in its regulation. Although 5 of the 12 QTLs are considered to be skeleton-wide loci and commonly affect both femurs and vertebrae, each of the bone sites also exhibited unique QTLs. Thus, the BMD phenotype can be partitioned into its genetic components and the effects of these loci on normal bone biology can be determined. Importantly, the BMD QTLs that we have identified are in regions of the mouse genome that have known human homology, and the QTLs will become useful experimental tools for mechanistic and therapeutic analyses of bone regulatory genes.

Genetic maps provide a means to estimate the probability of the co-inheritance of linked loci as they are transmitted across generations in both experimental and natural populations. However, in the age of whole-genome sequences, physical distances measured in base pairs of DNA provide the standard coordinates for navigating the myriad features of genomes. Although genetic and physical maps are colinear, there are well-characterized and sometimes dramatic heterogeneities in the average frequency of meiotic recombination events that occur along the physical extent of chromosomes. There also are documented differences in the recombination landscape between the two sexes. We have revisited high-resolution genetic map data from a large heterogeneous mouse population and have constructed a revised genetic map of the mouse genome, incorporating 10,195 single nucleotide polymorphisms using a set of 47 families comprising 3546 meioses. The revised map provides a different picture of recombination in the mouse from that reported previously. We have further integrated the genetic and physical maps of the genome and incorporated SSLP markers from other genetic maps into this new framework. We demonstrate that utilization of the revised genetic map improves QTL mapping, partially due to the resolution of previously undetected errors in marker ordering along the chromosome.

TWEAK cytokine has been implicated in several biological responses including inflammation, angiogenesis, and osteoclastogenesis. We have investigated the role of TWEAK in regulating skeletal muscle mass. Addition of soluble TWEAK protein to cultured myotubes reduced the mean myotube diameter and enhanced the degradation of specific muscle proteins such as CK and MyHCf. The effect of TWEAK on degradation of MyHCf was stronger than its structural homologue, TNF-alpha. TWEAK increased the ubiquitination of MyHCf and the transcript levels of atrogin-1 and MuRF1 ubiquitin ligases. TWEAK inhibited phosphorylation of Akt kinase and its downstream targets GSK-3beta, FOXO1, mTOR, and p70S6K. Furthermore, TWEAK increased the activation of NF-kappaB transcription factor in myotubes. Adenoviral-mediated overexpression of IkappaB alpha deltaN (a degradation-resistant mutant of NF-kappaB inhibitory protein IkappaB alpha) in myotubes blocked the TWEAK-induced degradation of MyHCf. Chronic administration of TWEAK in mice resulted in reduced body and skeletal muscle weight with an associated increase in the activity of ubiquitin-proteasome system and NF-kappaB. Finally, muscle-specific transgenic overexpression of TWEAK decreased the body and skeletal muscle weight in mice. Collectively, our data suggest that TWEAK induces skeletal muscle atrophy through inhibition of the PI3K/Akt signaling pathway and activation of the ubiquitin-proteasome and NF-kappaB systems.

Research Article| January 01 1989 Phosphotyrosyl protein phosphatases K H W Lau; K H W Lau 1Department of Medicine and Biochemistry, Loma Linda University, and Mineral Metabolism Unit (151), Jerry L. Pettis Memorial Veterans' Hospital, Loma Linda, CA 92357, U.S.A. Search for other works by this author on: This Site PubMed Google Scholar J R Farley; J R Farley 1Department of Medicine and Biochemistry, Loma Linda University, and Mineral Metabolism Unit (151), Jerry L. Pettis Memorial Veterans' Hospital, Loma Linda, CA 92357, U.S.A. Search for other works by this author on: This Site PubMed Google Scholar D J Baylink D J Baylink 1Department of Medicine and Biochemistry, Loma Linda University, and Mineral Metabolism Unit (151), Jerry L. Pettis Memorial Veterans' Hospital, Loma Linda, CA 92357, U.S.A. Search for other works by this author on: This Site PubMed Google Scholar Biochem J (1989) 257 (1): 23–36. https://doi.org/10.1042/bj2570023 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share MailTo Twitter LinkedIn Cite Icon Cite Get Permissions Citation K H W Lau, J R Farley, D J Baylink; Phosphotyrosyl protein phosphatases. Biochem J 1 January 1989; 257 (1): 23–36. doi: https://doi.org/10.1042/bj2570023 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Journal Search Advanced Search This content is only available as a PDF. © 1989 London: The Biochemical society1989 Article PDF first page preview Close Modal You do not currently have access to this content.

Protracted critical illness is marked by protein wasting resistant to feeding, by accumulation of fat stores, and by suppressed pulsatile release of GH and TSH. We previously showed that the latter can be reactivated by brief infusion of GH-releasing peptide (GHRP-2) and TRH. Here, we studied combined GHRP-2 and TRH infusion for 5 days, which allowed a limited evaluation of the metabolic effectiveness of this novel trophic endocrine strategy. Fourteen patients (mean +/- SD age, 68 +/- 11 yr), critically ill for 40 +/- 28 days, were compared to a matched group of community-living control subjects at baseline and subsequently received 5 days of placebo and 5 days of GHRP-2 plus TRH (1 + 1 microg/kg x h) infusion in random order. At baseline, impaired anabolism, as indicated by biochemical markers (osteocalcin and leptin), was linked to hyposomatotropism [reduced pulsatile GH secretion, as determined by deconvolution analysis, and low GH-dependent insulin-like growth factor and binding protein (IGFBP) levels]. Biochemical markers of accelerated catabolism (increased protein degradation and bone resorption) were related to tertiary hypothyroidism and the serum concentration of IGFBP-1, but not to hyposomatotropism. Metabolic markers were independent of elevated serum cortisol. After 5 days of GHRP-2 plus TRH infusion, osteocalcin concentrations increased 19% vs. -6% with placebo, and leptin had rose 32% vs. -15% with placebo. These anabolic effects were linked to increased IGF-I and GH-dependent IGFBP, which reached near-normal levels from day 2 onward. In addition, protein degradation was reduced, as indicated by a drop in the urea/creatinine ratio, an effect that was related to the correction of tertiary hypothyroidism, with near-normal thyroid hormone levels reached and maintained from day 2 onward. Concomitantly, a spontaneous tendency of IGFBP-1 to rise and of insulin to decrease was reversed. Cortisol concentrations were not detectably altered. In conclusion, 5-day infusion of GHRP-2 plus TRH in protracted critical illness reactivates blunted GH and TSH secretion, with preserved pulsatility, peripheral responsiveness, and feedback inhibition and without affecting serum cortisol, and induces a shift toward anabolic metabolism. This provides the first evidence of the metabolic effectiveness of short term GHRP-2 plus TRH agonism in this particular wasting condition.

ABSTRACT Eight normal young adult sleepers spent 4 nonconsecutive weeks in the laboratory. Each week consisted of a baseline night followed by 2 consecutive nights of disrupted sleep, followed by 2 recovery nights. Disruption conditions included: a) brief awakening after each minute of accumulated sleep, b) brief awakening after each 10 min of accumulated sleep, c) 2.5 hrs of normal sleep followed by a brief awakening at each sleep onset, and d) total sleep deprivation. Morning testing revealed that all disruption conditions decreased sleep latency in a morning nap test. Performance after 1‐min disruptions approximated that seen after total sleep loss. Performance decrements were less in the 10‐min condition and least in the 2.5‐hr sleep condition. Performance under baseline and total sleep loss conditions was used to predict performance during the sleep deprivation condition using four sleep stage rules. Total time asleep and total time asleep minus stage 1 predicted performance poorly. Total SWS plus REM predicted performance best but could not differentiate the 10‐min and 2.5‐hr conditions. Therefore, it was concluded that the data were most parsimoniously explained by the Sleep Continuity Theory—i.e., that periods of uninterrupted sleep in excess of 10 min are required for sleep to be restorative.

Vitamin C is an important antioxidant and cofactor that is involved in the regulation of development, function, and maintenance of several cell types in the body. Deficiencies in vitamin C can lead to conditions such as scurvy, which, among other ailments, causes gingivia, bone pain, and impaired wound healing. This review examines the functional importance of vitamin C as it relates to the development and maintenance of bone tissues. Analysis of several epidemiological studies and genetic mouse models regarding the effect of vitamin C shows a positive effect on bone health. Overall, vitamin C exerts a positive effect on trabecular bone formation by influencing expression of bone matrix genes in osteoblasts. Recent studies on the molecular pathway for vitamin C actions that include direct effects of vitamin C on transcriptional regulation of target genes by influencing the activity of transcription factors and by epigenetic modification of key genes involved in skeletal development and maintenance are discussed. With an understanding of mechanisms involved in the uptake and metabolism of vitamin C and knowledge of precise molecular pathways for vitamin C actions in bone cells, it is possible that novel therapeutic strategies can be developed or existing therapies can be modified for the treatment of osteoporotic fractures.

Insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) has been shown to inhibit IGF-dependent cell proliferation in a number of in vitro studies. However, no in vivo model of IGFBP-2 overexpression has been established so far. Therefore, we have generated transgenic mice, in which expression of a mouse IGFBP-2 complementary DNA is controlled by the cytomegalovirus (CMV) promoter. In two independent transgenic strains, transgene expression was highest in pancreas and stomach, followed by skeletal muscle, heart, colon, spleen, adipose tissue, brain, and kidney. Within the pancreas, IGFBP-2 expression was found in the islets but not in the exocrine part. Serum IGFBP-2 levels of CMV-IGFBP-2 transgenic mice were about 3-fold (P < 0.05) increased, compared with controls, whereas serum levels of IGF-I and IGF-II were unaffected by IGFBP-2 overexpression. Fasted serum glucose and fasted insulin levels were slightly reduced in transgenic mice, compared with controls. Postprandial serum glucose insulin levels were not affected by the genotype. At days later than 23, body weights of transgenic mice were significantly (P < 0.05) reduced in both sexes, compared with nontransgenic littermates. This reduction in body weight was mainly attributable to significantly (P < 0.05) lower carcass weights of CMV-IGFBP-2 transgenic vs. control mice. In contrast, absolute organ weights were not (or only as a tendency) reduced, except for the weight of the spleen, which was significantly (P < 0.05) lower in male transgenic than in control mice. Our data suggest that IGFBP-2 represents a negative regulator of postnatal growth in mice, potentially by reducing the bioavailability of IGF-I.