Insulin-like Growth Factor Family Members Research Articles

Insulin-like growth factor family and prostate cancer: new insights and emerging opportunities.

Prostate cancer is the second most commonly diagnosed cancer in men. The mammalian insulin-like growth factor (IGF) family is made up of three ligands (IGF-I, IGF-II, and insulin), three receptors (IGF-I receptor (IGF-1R), insulin receptor (IR), and IGF-II receptor (IGF-2R)), and six IGF-binding proteins (IGFBPs). IGF-I and IGF-II were identified as potent mitogens and were previously associated with an increased risk of cancer development including prostate cancer. Several reports showed controversy about the expression of the IGF family and their connection to prostate cancer risk due to the high degree of heterogeneity among prostate tumors, sampling bias, and evaluation techniques. Despite that, it is clear that several IGF family members play a role in prostate cancer development, metastasis, and androgen-independent progression. In this review, we aim to expand our understanding of prostate tumorigenesis and regulation through the IGF system. Further understanding of the role of IGF signaling in PCa shows promise and needs to be considered in the context of a comprehensive treatment strategy.

Mendelian randomization provides evidence for a causal effect of serum insulin-like growth factor family concentration on risk of atrial fibrillation.

Atrial fibrillation (AF) is one of the most common persistent arrhythmias among adult cardiovascular diseases. It is important to identify potential risk factors for AF. Members of the insulin-like growth factor (IGF) family exert a variety of effects on various cell types in the context of the pathogenesis of cardiovascular diseases, and previous population-based studies indicate associations between IGF family members and AF. However, the causal effects of IGF family members in AF have not been evaluated. In the current study two-sample Mendelian Randomization (MR) was used to assess genetic relationships between IGF family members and AF. MR was performed based on genome-wide association study (GWAS) datasets, and concentration levels of 14 IGF family members were retrieved. An initial MR analysis was conducted to identify single nucleotide polymorphisms potentially associated with IGF serum concentrations. A GWAS meta-analysis including 60620 AF cases and 970216 control participants of European ancestry was then conducted to identify AF causal effects. Two-sample MR packages were used to perform MR analysis in R. MR-Egger, weighted median (WM), and inverse variance weighted (IVW) methods were used. In two-sample MR assessments there were lower levels of circulating IGF binding protein 3 in both WM [odds ratio (OR) 0.964, 95% confidence interval (CI) 0.940-0.960, P = 0.006] and IVW (OR 0.968, 95%CI: 0.947-0.987, P = 0.001) analyses. Higher serum levels of IGF2 receptor were associated with AF (OR 1.045, 95%CI: 1.016-1.076, P = 0.039). In reverse MR analysis conducted to investigate casual effects, elevated levels of circulating CYR61 were associated with AF (OR 1.060, 95%CI: 1.005-1.119, P = 0.031). The results of the present study provide novel insights into the pathogenesis of AF, and the implications of serum IGF family member concentrations when assessing the risk of AF. The study generated evidence on the potential roles of developmental pathological effects in the pathogenesis of AF. Further observational and experimental studies are critically needed.

IGFs in Dentin Formation and Regeneration: Progress and Remaining Challenges.

Tertiary dentin results from the interplay between the host defense and dental injury or infection. Modern endodontics aiming vital pulp treatment take the tertiary dentin formation as the interim step, with the final goal of a physiological pulp-dentin like tissue regeneration. Dental pulp stem cells have been nominated for contributing to differentiating into odontoblast-like cells who are responsible for reparative dentin formation. Understanding the original dentin formation mechanism provides us a blueprint while exploring the reparative dentin formation mechanism builds bridge to bonafide pulp-dentin tissue regeneration. Among all the regulators, growth factors have long been revealed under the spotlight. The insulin-like growth factor (IGF) family has been implicated in critical events of inducing dentin formation, which is essential for pulp treatment. The expression of IGF family members including IGF1, IGF1R, IGF2, and IGF2R has been well characterized in dental papilla cells, dental pulp stem cells, and periodontal ligament cells. Recent studies indicated IGF binding to the receptors activated pathways, including MAPK pathway, and AKT pathway, orchestrated proliferation, and differentiation, and finally, contributed to dentin formation. This review summarizes the role of IGF family in dentin formation during tooth development and tertiary dentin formation during dentin-pulp repair and sheds light on key parts of research for future treatment improvements.

Impact of Long-Term HFD Intake on the Peripheral and Central IGF System in Male and Female Mice.

The insulin-like growth factor (IGF) system is responsible for growth, but also affects metabolism and brain function throughout life. New IGF family members (i.e., pappalysins and stanniocalcins) control the availability/activity of IGFs and are implicated in growth. However, how diet and obesity modify this system has been poorly studied. We explored how intake of a high-fat diet (HFD) or commercial control diet (CCD) affects the IGF system in the circulation, visceral adipose tissue (VAT) and hypothalamus. Male and female C57/BL6J mice received HFD (60% fat, 5.1 kcal/g), CCD (10% fat, 3.7 kcal/g) or chow (3.1 % fat, 3.4 kcal/g) for 8 weeks. After 7 weeks of HFD intake, males had decreased glucose tolerance (p < 0.01) and at sacrifice increased plasma insulin (p < 0.05) and leptin (p < 0.01). Circulating free IGF1 (p < 0.001), total IGF1 (p < 0.001), IGF2 (p < 0.05) and IGFBP3 (p < 0.01) were higher after HFD in both sexes, with CCD increasing IGFBP2 in males (p < 0.001). In VAT, HFD reduced mRNA levels of IGF2 (p < 0.05), PAPP-A (p < 0.001) and stanniocalcin (STC)-1 (p < 0.001) in males. HFD increased hypothalamic IGF1 (p < 0.01), IGF2 (p < 0.05) and IGFBP5 (p < 0.01) mRNA levels, with these changes more apparent in females. Our results show that diet-induced changes in the IGF system are tissue-, sex- and diet-dependent.

The IGF/Insulin-IGFBP Axis in Corneal Development, Wound Healing, and Disease.

The insulin-like growth factor (IGF) family plays key roles in growth and development. In the cornea, IGF family members have been implicated in proliferation, differentiation, and migration, critical events that maintain a smooth refracting surface that is essential for vision. The IGF family is composed of multiple ligands, receptors, and ligand binding proteins. Expression of IGF type 1 receptor (IGF-1R), IGF type 2 receptor (IGF-2R), and insulin receptor (INSR) in the cornea has been well characterized, including the presence of the IGF-1R and INSR hybrid (Hybrid-R) in the corneal epithelium. Recent data also indicates that each of these receptors display unique intracellular localization. Thus, in addition to canonical ligand binding at the plasma membrane and the initiation of downstream signaling cascades, IGF-1R, INSR, and Hybrid-R also function to regulate mitochondrial stability and nuclear gene expression. IGF-1 and IGF-2, two of three principal ligands, are polypeptide growth factors that function in all cellular layers of the cornea. Unlike IGF-1 and IGF-2, the hormone insulin plays a unique role in the cornea, different from many other tissues in the body. In the corneal epithelium, insulin is not required for glucose uptake, due to constitutive activation of the glucose transporter, GLUT1. However, insulin is needed for the regulation of metabolism, circadian rhythm, autophagy, proliferation, and migration after wounding. There is conflicting evidence regarding expression of the six IGF-binding proteins (IGFBPs), which function primarily to sequester IGF ligands. Within the cornea, IGFBP-2 and IGFBP-3 have identified roles in tissue homeostasis. While IGFBP-3 regulates growth control and intracellular receptor localization in the corneal epithelium, both IGFBP-2 and IGFBP-3 function in corneal fibroblast differentiation and myofibroblast proliferation, key events in stromal wound healing. IGFBP-2 has also been linked to cellular overgrowth in pterygium. There is a clear role for IGF family members in regulating tissue homeostasis in the cornea. This review summarizes what is known regarding the function of IGF and related proteins in corneal development, during wound healing, and in the pathophysiology of disease. Finally, we highlight key areas of research that are in need of future study.

Rumen-Protected Glucose Stimulates the Insulin-Like Growth Factor System and mTOR/AKT Pathway in the Endometrium of Early Postpartum Dairy Cows.

Simple SummaryA rapid recovery of the uterus is important in order to shorten the interval between pregnancies. An insufficient availability of glucose in early lactation can delay the uterine recovery. However, little information is available on dietary rumen-protected glucose addition on the uterine involution and insulin-like growth factor system in the endometrium of dairy cows during the early post-natal period. In this study, dairy cows were fed with 0 or 200 g rumen-protected glucose twice every day from −7 ± 2 to 14 d during the post-natal period. The results indicated that dietary rumen-protected glucose addition promoted the proliferation of endometrial cells in postpartum dairy cows by stimulating the insulin-like growth factor system and rapamycin complex 1 pathway, and might be beneficial for uterine recovery. This study aimed to elucidate the effects of a dietary rumen-protected glucose (RPG) addition on uterine involution through the analysis of an insulin-like growth factor (IGF) system and associated pathways in the post-natal endometrium. Twelve Holstein cows were assigned equally to two groups: a control group (CT) and an RPG group (200 g of RPG per cow per day). The plasma content of insulin-like growth factor 1 (IGF1) was determined by using the ELISA method. Expressions of IGF members, the matrix metalloproteinase, protein kinase B (AKT)/mechanistic target of rapamycin complex1 (mTOR) signaling pathway, and cell proliferation factors (proliferating cell nuclear antigen (PCNA) and Ki67) were detected using real-time polymerase chain reaction, Western blot, immunohistochemistry, and immunofluorescence, respectively. The results showed that the positive cells of PCNA and Ki67 were increased in the endometrium of RPG versus CT cows. The RPG addition significantly increased the plasma IGF1 level 14 d after delivery. The mRNA expressions of the IGF family members (IGF1, IGF2, type 1 IGF receptor (IGF1R) and IGF-binding proteins (IGFBP1, IGFBP2, IGFBP4 and IGFBP5)) were upregulated, and mRNA expressions of matrix metalloproteinase MMP3 and MMP9 were downregulated in cows from the RPG group compared with the CT group. Meanwhile, the protein expressions of IGF1, IGF2, IGF1R, IGFBP1 and IGFBP4 were upregulated in cows from the RPG group compared with the CT group. Immunohistochemical analysis identified a positive response for IGF1R and IGF2R in the endometrium of RPG versus CT cows. Furthermore, the RPG supplementation increased the protein expressions of phosphorylated (p)-AKT to total AKT and p-mTOR to total mTOR ratio in the endometrium. The current results indicated that the RPG supplementation promoted the proliferation of endometrial cells by stimulating the IGFs and mTOR/AKT pathway in the early post-natal endometrium of dairy cows.

IGF paracrine and autocrine interactions between conceptus and oviduct

Development in vitro is influenced by embryo density, serum, somatic cell co-culture and the production of 'embryotrophic' paracrine and autocrine factors. Research in our laboratory has focussed principally on the insulin-like growth factor (IGF) family. We have demonstrated that pre-attachment bovine and ovine embryos express mRNAs encoding a number of growth factor ligand and receptor genes including all members of the IGF ligand and receptor family throughout this developmental interval. In addition, early embryos express mRNAs encoding IGF-binding proteins (IGFBPs) 2-5 from the one-cell to the blastocyst stage and IGFBP5 mRNA at the blastocyst stage. Cultured bovine blastocysts release up to 35 pg per embryo in 24 h, whereas release of IGF-I was below detectable values. Analysis extended to bovine oviductal cultures has also demonstrated that mRNAs encoding these IGF family members are present throughout an 8 day culture period. Transcripts encoding IGFBPs 2-6 were also present. Release of both IGFs was recorded over an 8 day culture period. IGF-II release was significantly greater than that observed for IGF-I. Therefore, the IGFs are present throughout the maternal environment during early embryo development. The oocyte, within the follicle, is held in an environment high in IGFs and IGFBPs. The zygote, after fertilization, is maintained in an IGF-rich environment while free-living in the oviduct and the uterus. This review is focused on the IGF family and IGFBPs and their roles in enhancing development up to the blastocyst stage.

Differential expression of insulin-like growth factor family members in immature cumulus-oocyte complexes from dairy cows with different genotypes.

It has been evident the improvement of in vitro embryo production (IVEP) in dairy cows. Nevertheless, it is known that differences in the number and quality of oocytes between taurine and zebu females impact the efficiency and economic viability of IVEP. As the insulin-like growth factor (IGF) system is related to follicular and oocyte development, we aimed to quantify mRNA abundance of IGF system members and pregnancy-associated plasma protein-A (PAPPA) in the cumulus-oocyte complexes (COCs) of Gir, 1/2 Holstein×1/2 Gir and Holstein cows. Four pools of 30 immature COCs from Gir, 1/2 Holstein×1/2 Gir and Holstein cows were obtained by ovum pickup (OPU), and the oocytes and cumulus cells (CC) were mechanically separated and stored at -80°C. Total RNA was extracted from pools of 30 oocytes and their respective CC. Expression of target genes was assessed by real-time RT-PCR. In oocytes, the abundance of IGFR1 mRNA was higher (p<.05) in Gir cows compared with the other breeds. In contrast, in CC, mRNA encoding IGF2 (p<.05), IGFR2 (p<.05) and IGFBP4 (p<.01) was higher in Holstein donors compared with Gir and 1/2 Holstein×1/2 Gir cows. Additionally, the abundance of PAPPA mRNA was higher in oocytes (p<.001) and CC (p<.01) in Gir and 1/2 Holstein×1/2 Gir cows compared with the Holstein donors. In conclusion, the higher abundance of PAPPA mRNA in the oocytes and CC from Gir and cross-breed donors combined with the low expression of IGFBP4 in the CC suggests an enhancement of the bioavailability of IGF-free when compared with Holstein COCs.

The Role of Parathyroid Hormone-Related Protein (PTHrP) in Osteoblast Response to Microgravity: Mechanistic Implications for Osteoporosis Development.

Prolonged skeletal unloading through bedrest results in bone loss similar to that observed in elderly osteoporotic patients, but with an accelerated timeframe. This rapid effect on weight-bearing bones is also observed in astronauts who can lose up to 2% of their bone mass per month spent in Space. Despite the important implications for Spaceflight travelers and bedridden patients, the exact mechanisms involved in disuse osteoporosis have not been elucidated. Parathyroid hormone-related protein (PTHrP) regulates many physiological processes including skeletal development, and has been proposed as a mechanosensor. To investigate the role of PTHrP in microgravity-induced bone loss, trabecular and calvarial osteoblasts (TOs and COs) from Pthrp +/+ and -/- mice were subjected to actual Spaceflight for 6 days (Foton M3 satellite). Pthrp +/+, +/- and -/- osteoblasts were also exposed to simulated microgravity for periods varying from 6 days to 6 weeks. While COs displayed little change in viability in 0g, viability of all TOs rapidly decreased in inverse proportion to PTHrP expression levels. Furthermore, Pthrp+/+ TOs displayed a sharp viability decline after 2 weeks at 0g. Microarray analysis of Pthrp+/+ TOs after 6 days in simulated 0g revealed expression changes in genes encoding prolactins, apoptosis/survival molecules, bone metabolism and extra-cellular matrix composition proteins, chemokines, insulin-like growth factor family members and Wnt-related signalling molecules. 88% of 0g-induced expression changes in Pthrp+/+ cells overlapped those caused by Pthrp ablation in normal gravity, and pulsatile treatment with PTHrP1-36 not only reversed a large proportion of 0g-induced effects in Pthrp+/+ TOs but maintained viability over 6-week exposure to microgravity. Our results confirm PTHrP efficacy as an anabolic agent to prevent microgravity-induced cell death in TOs.

IGF-binding protein 2 is a candidate target of therapeutic potential in cancer.

Insulin-like growth factor (IGF)-binding protein 2(IGFBP2), a key member of IGF family, has been reported as a notable oncogene in most human epithelium cancers. Increasing evidences suggested that IGFBP2 might be a candidate target of therapuetic potential by regulating key cancer metastasis and invasion-associated signaling networks, but there is still confusion about the mechanism on how IGFBP2 takes part in these processes. In this review, we summarized the current points of view that IGFBP2 functions in signaling pathways during tumorigenesis and tumor progression and discussed its potential clinical applications as a therapeutic target.

Expression and localization of insulin-like growth factor system in corpus luteum during different stages of estrous cycle in water buffaloes (Bubalus bubalis) and the effect of insulin-like growth factor I on production of vascular endothelial growth factor and progesterone in luteal cells cultured in vitro

This study investigated the expression and localization of insulin-like growth factor (IGF) system at different stages of buffalo CL and the role of IGF-I in stimulating vascular endothelial growth factor (VEGF) and progesterone (P4) production in cultured luteal cells. The mRNA expression of IGF system, VEGF, steroidogenic acute regulatory protein, P450scc, and hydroxysteroid dehydrogenase (HSD) was investigated by quantitative real-time polymerase chain reaction (PCR). Protein expression of IGF was demonstrated by Western blot and localization by immunohistochemistry. Progesterone and VEGF production was assayed using RIA and ELISA. A relatively high mRNA expression of IGF-I and IGF-II in early, mid- and late luteal phases with immunoreactivity mostly restricted to cytoplasm of large luteal cells indicates their autocrine role, whereas very weak immunoreactivity in endothelial cells during the mid-luteal phase indicates their paracrine role. Insulin-like growth factor receptors, IGF-IR and IGF-IIR, were restricted to large luteal cells with high mRNA and protein expressions in the mid-luteal phase. The significantly higher expression of insulin-like growth factor binding protein (IGFBP)-1, -3, -5, and -6 in the early or mid-luteal phase suggested their stimulatory role, whereas that of IGFBP-2 and -4 in mid-, late, and regressive luteal stages implied their inhibitory role. The mRNA expressions of key steroidogenic factors and VEGF were significantly higher (P < 0.05) when the culture medium was supplemented with 100 ng/mL of IGF-I for 72 hours. Moreover, IGF-I at a dose of 100 ng/mL increased P4 and VEGF production (P < 0.05). It can be concluded that IGF family members via their autocrine and paracrine effect play significant roles in promoting angiogenesis through the production of VEGF in luteal cells and steroid synthesis through the production of key steroidogenic factors.

Development of IGF Signaling Antibody Arrays for the Identification of Hepatocellular Carcinoma Biomarkers

PurposeOur objective was to develop a system to simultaneously and quantitatively measure the expression levels of the insulin-like growth factor (IGF) family proteins in numerous samples and to apply this approach to profile the IGF family proteins levels in cancer and adjacent tissues from patients with hepatocellular carcinoma (HCC).Experimental DesignAntibodies against ten IGF family proteins (IGF-1, IGF-1R, IGF-2, IGF-2R, IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-6, and Insulin) were immobilized on the surface of a glass slide in an array format to create an IGF signaling antibody array. Tissue lysates prepared from patient's liver cancer tissues and adjacent tissues were then applied to the arrays. The proteins captured by antibodies on the arrays were then incubated with a cocktail of biotinylated detection antibodies and visualized with a fluorescence detection system. By comparison with standard protein amount, the exact protein concentrations in the samples can be determined. The expression levels of the ten IGF family proteins in 25 pairs of HCC and adjacent tissues were quantitatively measured using this novel antibody array technology. The differential expression levels between cancer tissues and adjacent tissues were statistically analyzed.ResultsA novel IGF signaling antibody array was developed which allows the researcher to simultaneously detect ten proteins involved in IGF signal pathway with high sensitivity and specificity. Using this approach, we found that the levels of IGF-2R and IGFBP-2 in HCC tissues were higher than those in adjacent tissues.ConclusionOur IGF signaling antibody array which can detect the expression of ten IGF family members with high sensitivity and specificity will undoubtedly prove a powerful tool for drug and biomarker discovery.

Expression of Insulin-like Growth Factor (IGF) Family Members in Porcine Pregnancy

Prenatal mortality is a prime concern for commercial swine industry in North America. Fetal losses occur throughout gestation but cluster in early (~day20) and mid (~day50) pregnancy. Adequate vascularization of the attachment site has emerged as a key factor contributing to fetal success. Since Insulin-Like Growth Factor (IGF) family members regulate angiogenesis in addition to promoting fetal development and growth, we hypothesized that conceptus success is governed by members of the IGF family. Using quantitative real time PCR, we analyzed expression of IGF family members (IGF-I, IGF-II, IGF-I Receptor (IGF-IR), IGF-IIR and their binding proteins, IGFBPs) in matched maternal and fetal tissues of healthy and arresting conceptuses at gestation days (gd) 20 and 50. IGF-II transcripts were 100 fold increased in both maternal and fetal tissues compared to IGF-I, but receptor transcripts were found in similar abundance irrespective of health status and gestation point. IGFBP3 was the most abundantly transcribed of the binding proteins. Using immunohistochemistry we confirmed the expression of IGF family members in maternal luminal and glandular epithelial cells, the endothelium of blood vessels and some scattered stromal cells. Our results suggest that IGF-I and II and their receptors are differentially expressed at the maternal and fetal components of the attachment site.

The Interplay of Insulin-Like Growth Factors, Gonadotropins, and Endocrine Disruptors in Ovarian Follicular Development and Function

Over the past 20 years, the expression, signaling mechanisms, and roles of members of the insulin-like growth factor (IGF) family (ligands, receptors, binding proteins, and binding protein proteases and their inhibitors) have been elucidated in ovarian follicle function in humans and other species. In vitro studies with human, nonhuman primate, and farm animal granulosa and thecal cells and genetic approaches using mouse knockout models for IGF family members have revealed that IGFs are key intraovarian regulators of follicle growth, selection, atresia, cellular differentiation, and steroidogenesis, oocyte maturation, and cumulus expansion. Some of these actions are synergistic with gonadotropins, although most are not sustainable with IGFs alone and require gonadotropin actions, thereby designating IGFs as "co-gonadotropins." In the human disorder of polycystic ovarian syndrome, characterized by small antral follicle arrest, the IGF system appears to contribute to the observed resistance to follicle-stimulating hormone action at the level of the granulosa compartment and the persistence of an androgen-dominant milieu in the arrested follicles. Interestingly, recent studies demonstrate that endocrine-disrupting chemicals can compromise IGF activity and signaling in the ovarian follicle, affecting follicle development, steroidogenesis, and oocyte quality. The successful development of a healthy oocyte and appropriate granulosa and theca cell steroidogenesis on a cyclic basis are contingent on multiple factors, including a properly functioning intraovarian IGF system. Disruption of even one component of this system can lead to abnormal follicular development and function and compromised reproductive capacity.

Interrelationships between negative energy balance (NEB) and IGF regulation in liver of lactating dairy cows

In dairy cows, negative energy balance (NEB) during the early post-partum period is associated with major alterations in the growth hormone-insulin-like growth factor (GH-IGF) axis. Since the liver mediates nutrient partitioning during lactation, we aimed to determine how NEB alters the endocrine regulation of the insulin-like growth factor (IGF) system by investigating the expression of IGF family members and related steroid receptors. On the second day of lactation, cows were allocated to one of two treatments designed to produce mild (MNEB) or severe NEB (SNEB). MNEB cows ( n = 5) were fed ad lib grass silage supplemented with concentrate and milked x1 daily and SNEB cows ( n = 6) were restricted in dietary intake and milked x3 daily. Energy balance (EB) status was monitored until the second week of lactation when plasma and liver samples revealed a markedly divergent metabolic profile. At this time, plasma protein and hepatic mRNA for IGF-I was reduced in SNEB cows compared with MNEB cows. Both levels of expression correlated highly when data from all animals was pooled ( r = 0.963; P < 0.01). SNEB cows also exhibited reduced hepatic expression for transcripts encoding IGF-1R, IGF-2R, IGF binding proteins (IGFBPs) -3, -4, -5, -6, acid labile subunit, and receptors for oestrogen (ERα) and growth hormone (total GHR and 1A variant), while the expression of IGFBP-2 was elevated. Expression of mRNA for IGF-II, IGFBP-1 and receptors for insulin (A/B) and glucocorticoid (α) was unaffected by EB. Results demonstrate that SNEB affects hepatic synthesis of IGF-I, and other components known to modulate the bioavailability and stability of circulating IGF-I.

Ovarian function in ruminants

The purpose of this overview is to highlight important steps of ovarian regulation during follicle development, ovulation and the life span of corpus luteum (CL) in ruminants. The ovarian cycle is central to reproductive function. It is characterized by repeating patterns of cellular proliferation, differentiation and transformation that encompass follicular development and ovulation as well as the formation, function and regression of the CL. In the first part, the importance and regulation of final follicle growth and especially of angiogenesis and blood flow during folliculogenesis, dominant follicle development and CL formation are described. Our results underline the importance of growth factors especially of insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) for development and completion of a dense network of capillaries (angiogenesis) during follicle growth and CL formation. In the second part, the regulation of CL function by endocrine/paracrine and autocrine acting regulators is discussed. There is evidence that besides the main endocrine hormones luteinizing hormone (LH) and growth hormone (GH) local regulators as growth factors, peptides, steroids and prostaglandins are important modulators of luteal function. During early CL development until midluteal stage oxytocin (OT), prostaglandins and progesterone (P) itself stimulate luteal cell proliferation and function supported by the luteotropic action of a number of growth factors. The still high mRNA expression, protein concentration and localization of VEGF, FGF and IGF family members in the cytoplasm of luteal cells during midluteal stage suggest that they play pivotal role in the maintenance (survival) of this endocrine tissue. The major function of the CL is to secrete P. Progesterone itself regulates the length of the estrous cycle via influencing the timing of the luteolytic PGF2α signal from the endometrium. At the end of a nonfertile cycle, the regression of CL commences, steroidogenic capacity is lost (functional luteolysis), cell death is initiated, and tissue involution as well as resorption occurs within a few days (structural luteolysis). The cascade of mediators during luteolysis is very complex and still awaits elucidation. Evidence is given for participation of blood flow, inflammatory cytokines, vasoactive peptides (angiotensin II and endothelin-1), and decrease of the classical luteotropic mediators.

Distinct expression pattern of insulin‐like growth factor family in rodent taste buds

The insulin-like growth factor (IGF) system is an important regulator of growth and differentiation in a variety of tissues. In the present study, the expression of IGF family members in the taste buds of mice and rats was examined. By reverse transcriptase polymerase chain reaction (RT-PCR) analysis, mRNA of IGF-I and -II, IGF-I receptor (IGF-IR), insulin receptor (insulin R), and IGF-binding protein (IGFBP)-2, -3, -4, -5, and -6 was detected in the taste bud-containing epithelium of the circumvallate papillae of mice. As suggested by the study using degenerate PCR (McLaughlin [2000] J. Neurosci. 20:5679-5688), IGF-IR was expressed in most of the taste bud cells of adult mice, as found by immunohistochemistry, and in those of postnatal day (P) 6 mice by in situ hybridization. Insulin R, which has strong homology to IGF-IR, was also detected in most of the taste bud cells of mice by immunohistochemistry and in situ hybridization. IGF-I immunoreactivity was detected in a few taste bud cells and in the epithelium surrounding taste buds. Northern blot analysis revealed that the amount of IGF-I mRNA in taste bud-containing epithelium was very low compared with that in liver. IGF-II immunoreactivity was weakly detected in mouse taste buds and the surrounding epithelium. In the rat tissue, a subset of the taste bud cells was positive for IGF-II. Among the six IGFBPs, IGFBP-2, -5, and -6 were detected in the mouse taste buds: IGFBP-2 and -5 immunoreactivity was seen in the majority of the taste bud cells, whereas IGFBP-6 immunoreactivity was found in the nerve fibers innervating the taste buds. In situ hybridization study also revealed that IGFBP-2 and -5 mRNA was synthesized in the taste buds of P6 mice and that the expression of these mRNAs overlapped in von Ebner's glands. These data reveal that IGF-I and -II might be produced in taste bud cells and (or) surrounding lingual epithelium and act through IGF-IR and insulin R locally in a paracrine and autocrine manner. The activity of these IGFs may be modulated through their interaction with IGFBP-2, -5, and 6.

Aetiology and pathogenesis of benign prostatic hyperplasia.

Prostatic hyperplasia predominantly involves the stromal compartment of the gland and affects more than 70% of men of 70 years or older with or without obstructive symptoms of benign prostatic hyperplasia. A consensus view is emerging concerning the factors and control systems that modulate cell proliferation and connective tissue biology in the prostate. The purpose of this review is to discuss some of the recent work contributing to the latter in the context of the aetiology of benign prostatic hyperplasia. Studies over the last 3-5 years have identified transforming growth factor beta, fibroblast growth factor and insulin-like growth factor family members as key regulators of cell proliferation and extracellular matrix turnover with interrelated activities. Recently, oestrogens, adrenergic signalling and inflammatory processes have been shown to impact and potentially perturb the balance between the activities of the above factors. These agents are all subject to alteration with age and as such are candidates for potential triggers of the initiation of stromal hyperplasia. The current model for the control and dysregulation of prostatic stromal growth is discussed in relation to the pathogenesis of benign prostatic hyperplasia and future directions for research.

IGF-II and IGFBP-1 reversely regulate blastocyst implantation in mouse

Insulin-like growth factor (IGF)-II and IGF binding protein (IGFBP)-1, members of IGF family, are important in the cyclic development of endometrium and the blastocyst implantation. In the present study, the indirect immunofluorescence showed that IGF-II and IGFBP-1 were specifically expressed at the maternal-fetal interface. In a co-culture system, IGF-II significantly enhanced the attachment and outgrowth of the blastocyst on monolayer of uterine epithelial cells, while IGFBP-1 did not affect the blastocyst attachment, but markedly inhibited the blastocyst outgrowth. The results of zymography showed that IGF-II enhanced the activities of MMP-2 and MMP-9, while IGFBP-1 did not affect the activities of MMP-2 and MMP-9. In conclusion, the equilibrium between the invasion of trophoblast and the inhibition of deciduas may be regulated by the interaction between the IGF-II-expressing invading cytotrophoblast and maternal deciduas-derived IGFBP-1.

The pathophysiology of benign prostatic hyperplasia.

The development of human benign prostatic hyperplasia and its related signs and symptoms clearly requires a combination of testicular androgens and aging. Although the role of androgens as a causative factor for human benign prostatic hyperplasia is debated, they undoubtedly play at least a permissive role. The principle prostatic androgen is dihydrotestosterone. Two isoenzymes of 5-alpha reductase have been discovered. Type 2 is dominant in the genital issue. Testosterone is reduced by the 5-a reductase to dihydrotestosterone. Benign prostatic hyperplasia is predominantly due to stromal hyperplasia of the gland and affects more than 70% of men of 70 years or older with or without obstruction. Recent studies identified transforming growth factor-b, fibroblast growth factor and insulin-like growth factor family members as key regulators of cell proliferation and extracellular matrix turnover with interrelated activities. Furthermore, estrogens, andenergic signaling and inflammatory processes have been shown to have an impact. Without a solid understanding of the physiology and pathophysiology of benign prostatic hyperplasia it can be difficult to interpret the results of clinical trials and symptoms.