Metalloproteinases (MMPs -2, -3) are involved in TGF-beta and IGF-1-induced bone defect healing in 20-month-old female rats

Matrix metalloproteinases are important in the physiological and pathological degradation of extracellular matrix including that of bone and cartilage. The process of bone defect healing is associated with formation of cartilage callus and cancelous bone. With maturation and aging, the response of skeletal tissues to injury is limited. The ability of growth factors to enhance bone defect healing in aged rats was studied. Partial bone defects were induced in femurs of aged rats. A single dose of IGF-1, TGF-beta+IGF-1 or saline was inserted in the defect and bones were examined after 2 and 4 weeks. Morphology revealed that after 2 weeks of treatment with TGF-beta the defects were filled with mesenchyme-like tissue and delicate bone trabeculae. Positive staining for metalloproteinase-2 (MMP-2) was shown at the sites of new bone formation. In defects treated with IGF-1 or TGF-beta+IGF-1 nodules of cartilage and fine bone trabeculae along with positive staining for both MMP-2 and MMP-3 were demonstrated in the healing defects. After 4 weeks radiology revealed mineralization in defects treated with TGF-beta and less pronounced mineralization after treatment with IGF-1, or with TGF-beta+IGF-1, whereas only partial healing of the defects was observed in control specimens. MMP-2 and MMP-3 were detected at sites of new bone formation after treatment with TGF-beta, IGF-1, and TGF-beta+IGF-1. It is concluded that TGF-beta and IGF-1 induced bone defect healing in aged rats. TGF-beta induced bone formation while IGF-1 induced cartilage and than bone formation via endochondral ossification. The localization of MMP-2 and MMP-3 in the healing defects reflected the synthesis of bone or cartilage matrices in the defect, reflecting the involvement of MMPs in the process of bone formation and endochondral ossification. The ability to induce bone defect healing in aging is of great clinical importance and understanding the involvement of MMPs in this process can contribute to future treatment with growth factors to enhance bone defect healing in 20-month-old female rats.     

Trifocal distraction osteogenesis for reconstruction of skull defect

ObjectiveTo apply trifocal distraction osteogenesis in canine model of skull segmental defects and to provide reference for clinical treatment.MethodsSix labrador dogs were selected in this study and divided into observation group and control group randomly. Each group contained 3 dogs. Skull segmental defects models were established by surgery, and dogs in bservation group received trifocal distraction osteogenesis treatment. Bone density was observed and compared between two groups during treatment.ResultsThere were no significant difference in bone density between two groups on th 1st day (P>0.05). The bone density of observation group on the 30th day, and 60th day were higher than that of control group (P<0.01).ConclusionsTrifocal distraction osteogenesis has significant clinical effect, and it would be widely used in clinical treatment.     

Different Effects of Growth Factors on Proliferation and Matrix Production of Normal and Fibrotic Human Lung Fibroblasts

Objectives and methods: In idiopathic pulmonary fibrosis (IPF), proliferation of fibroblasts and increased matrix deposition result in pulmonary damage and respiratory insufficiency. We cultured human fibroblasts from lung biopsies of healthy adults and of three patients with IPF (histologically usual interstital pneumonitis, UIP) in order to compare proliferation ([³H]thymidine incorporation, cell count) and matrix protein expression (immune fluorescence, quantification of fibronectin synthesis using time-resolved immune fluorescence) of normal and UIP fibroblasts in response to various growth factors. Findings: The growth factors platelet-derived growth factor-BB (PDGF), epidermal growth factor (EGF), insulin growth factor-1 (IGF-1), insulin-like growth factor-2 (IGF-2), tumor necrosis factor α (TNFα), Transforming growth factor-β (TGFβ₁), and fibroblast growth factor-2 (FGF-2) stimulate proliferation of normal lung fibroblasts significantly more than proliferation of UIP fibroblasts. Immunofluorescence reveals extensive expression of collagen I, collagen III, and fibronectin induced by serum, TGFβ₁, and TNFα. This expression is more pronounced in UIP fibroblasts than in normal fibroblasts. Quantification of fibronectin synthesis reveals an enhanced fibronectin synthesis by UIP fibroblasts in response to PDGF, EGF, IGF-1, IGF-2, TNFα, TGFβ₁, and FGF-2). Conclusions: Fibroblasts from normal and UIP lungs differ in their response to growth factors: Whereas normal fibroblasts show a predominantly proliferative response, UIP fibroblasts show an enhanced synthetic activity. Different fibroblast responses may contribute to progressive pulmonary fibrosis in patients with UIP.     

Increased levels of insulin-like growth factor binding protein-3 in hypertensive patientswith carotid atherosclerosis

BackgroundIt has been proven that the intima–media thickness (IMT) of the carotid artery increases in patients with essential hypertension. Serum levels of insulin-like growth factor-1 (IGF-1) increase in hypertensive patients with ventricular hypertrophy. However, the relationship between carotid atherosclerosis and serum levels of IGF-1 and its binding protein-3 (IGFBP-3) in patients with essential hypertension has not been established.MethodsThe carotid IMT, blood pressure (BP), serum lipid profiles, and serum IGF-1 and IGFBP-3 contents were determined in 54 hypertensive patients (19 with and 35 without carotid plaque) and 52 normotensive controls without plaque.ResultsSystolic, diastolic, and mean BPs and serum IGFBP-3 level were significantly higher in the hypertensive patients (with and without plaque) than in the normotensive controls. The IGFBP-3 level correlated with systolic BP (r = 0.204, P = .0354). Age, gender, body mass index, and serum levels of HDL cholesterol, triglycerides, lipoprotein(a), lipid peroxides, insulin, and fasting plasma glucose did not differ significantly among the three groups. Hypertensive patients with plaque, compared with those without plaque or the normotensive controls, had the highest values of carotid IMT, LDL cholesterol, IGF-1, and IGFBP-3. Multiple logistic regression analysis revealed that the IGFBP-3 level was associated with a ninefold (95% confidence interval 2.6–31) higher risk of carotid plaque formation compared with LDL cholesterol or IGF-1 levels.ConclusionsThese results suggest that an increased level of IGFBP-3 may play a crucial role in the development of carotid atherosclerosis in hypertensive patients.     

Insulin-Like Growth Factor-1 Receptor Targeted Fluorescent Imaging for Gallbladder Cancer in Orthotopic Mouse Models

Background/AimsGallbladder cancer is fatal, but fluorescent imaging technology can facilitate timely diagnosis and improve patient outcomes. Fluorophore-conjugated insulin-like growth factor-1 receptor (IGF-1R) targeted antibodies were used to visualize gallbladder cancer in orthotopic tumor mouse models.MethodsWestern blotting, flow cytometric analysis, and confocal microscopy detected the expression of IGF-1R in SNU-308, SNU-478, and SNU-1196 bile duct cancer cells. In vivo imaging of SNU-478 and SNU-1196 subcutaneous tumors and orthotopic gallbladder tumor models of SNU-478 were performed after injection with DyLight 650-conjugated IGF-1R antibody.ResultsWestern blotting and flow cytometric analysis showed that IGF-1R was expressed in bile duct cancer cells, and confocal microscopy demonstrated that IGF-1R antibody was able to bind to IGF-1R on the cell membrane. Fluorescent IGF-1R antibody injected into the mouse tail vein made subcutaneous tumors and orthotopic tumors become fluorescent. The intensity of fluorescence from the tumor was stronger than that from surrounding normal tissues. Histochemical examination confirmed that the tumor was located inside the gallbladder and adjacent liver parenchyma of mice.ConclusionsOur study showed that a fluorescent IGF-1R-targeted antibody could help detect gallbladder tumors. Tumor-specific imaging technology can be applied to endoscopy, laparoscopy, and robotic surgery for better management of gallbladder cancer.     

Acceleration of fracture healing in nonhuman primates by fibroblast growth factor-2

One of the greatest needs in the clinical bone field is a bioactive agent to stimulate bone formation. We previously reported that fibroblast growth factor-2 (FGF-2) exhibited strong anabolic actions on bone formation in models of rodents and dogs. Aiming at a clinical application, this study was undertaken to clarify the effect of a single local application of recombinant human FGF-2 on fracture healing in nonhuman primates. After a fracture was created at the midshaft of the right ulna of animals and stabilized with an intramedullary nail, gelatin hydrogel alone (n = 10) or gelatin hydrogel containing 200 microg FGF-2 (n = 10) was injected into the fracture site. Although 4 of 10 animals treated with the vehicle alone remained in a nonunion state even after 10 weeks, bone union was complete at 6 weeks in all 10 animals treated with FGF-2. Significant differences in bone mineral content and density at the fracture site between the vehicle and FGF-2 groups were seen at 6 weeks and thereafter. FGF-2 also increased the mechanical property of the fracture site. We conclude that FGF-2 accelerates fracture healing and prevents nonunion in primates, and therefore propose that it is a potent bone anabolic agent for clinical use.     

Promotion of corneal epithelial wound healing in diabetic rats by the combination of a substance P-derived peptide (FGLM-NH<Subscript>2</Subscript>) and insulin-like growth factor-1

AIMS/HYPOTHESIS: The healing of corneal epithelial wounds is often delayed in individuals with diabetes. The effect of the combination of a substance P-derived tetrapeptide (phenylalanine-glycine-leucine-methionine amide, or FGLM-NH(2)) and insulin-like growth factor-1 (IGF-1) on corneal epithelial wound healing was investigated in rats with streptozotocin-induced diabetes. METHODS: The corneal epithelium of diabetic and non-diabetic rats was removed, and the animals were treated by the application of eye drops containing FGLM-NH(2) and IGF-1, or vehicle alone as a control, six times a day for 3 days. The area of the corneal epithelial wound was measured at various times up to 72 h after removal of the corneal epithelium. RESULTS: The rate of corneal epithelial wound healing was slower in diabetic rats treated with vehicle than in non-diabetic rats. However, the rate of wound closure in diabetic rats treated with FGLM-NH(2) and IGF-1 was markedly increased compared with that in diabetic rats treated with vehicle. The wound healing process seemed similar in normal rats and in diabetic rats treated with FGLM-NH(2) and IGF-1. CONCLUSION/INTERPRETATION: The combination of FGLM-NH(2) and IGF-1 promotes corneal epithelial wound healing in diabetic rats, suggesting that such a treatment might prove effective in humans with diabetic keratopathy.     

Low levels of plasma IGF-1 inhibit intracortical bone remodeling during aging

Studies linking insulin-like growth factor-1 (IGF-1) to age-related bone loss in humans have been reported but remain only correlative. In this investigation, we characterized the bone phenotype of aged WT C57BL/6J male mice in comparison to that of C57BL/6J mice with reduced serum IGF-1 levels arising from an igfals gene deletion (ALS knockout (ALSKO)). During the aging process, WT mice showed an increase in fat mass and decrease lean mass while ALSKO mice had stable lean and fat mass values. Skeletal analyses of femora from WT mice revealed an expansion of the marrow area and a significant accumulation of intracortical porosity associated with increased intracortical remodeling. In contrast, ALSKO mice showed only small age-related declines in the amount of cortical bone tissue and minimal intracortical porosity, at 2 years of age. Accordingly, mechanical tests of femora from 2-year-old WT mice revealed reduced stiffness and maximal load when compared to bones from ALSKO mice. We show here that lifelong reductions in serum IGF-1 compromise skeletal size in development leading to slender bones; they are also associated with decreased intracortical bone remodeling and preservation of bone strength during aging.     

Enhancement of bone defect healing in old rats by TGF-beta and IGF-1

Bone defects are often created in order to repair bone pathologies. In the aging population, the healing of such defects is very limited. Bone healing in aging depends on the availability of various hormone and growth factors. The ability of growth factors to enhance bone formation in femoral defects in old rats was tested. Bone defects were induced in femurs of old rats. A single dose of transforming growth factor-beta (TGF-beta), IGF-1, TGF-beta+IGF-1 or saline was inserted in the defect and bones were tested after 2 and 4 weeks. Radiology revealed that mineralization appeared in the 2 weeks group in defects treated with TGF-beta and in defects treated with TGF-beta, TGF-beta+IGF-1 in the 4 weeks groups. Computerized tomography (CT) coronal and axial images revealed that 4 weeks after treatment with TGF-beta+IGF-1, a complete bone bridge was observed. Morphology revealed that these defects were filled with trabecular bone. A less pronounced bone healing was observed after TGF-beta or IGF-1, while control specimens revealed partial healing of the bone defect. Biomechanical tests indicated that treatment with TGF-beta, IGF-1 or TGF-beta+IGF-1 resulted in a significant increase of bone bending rigidity compared to control in the 4 weeks group and that TGF-beta+IGF-1 was the most inductive in this respect. The ability to induce bone healing in aging by TGF-beta+IGF-1 is of a great clinical importance for restoration of bone strength and biomechanical properties of bone defects in aging.     

Low peripheral levels of insulin growth factor-1 are associated with high incidence of delirium among elderly patients: A systematic review and meta-analysis

IntroductionDelirium, a serious condition observed in critically ill patients, clinically presents with impaired cognition and consciousness. The relationship between delirium and peripheral levels of insulin growth factor-1 (IGF-1) is unclear. Thus we conducted a meta-analysis to address this issue.MethodsSeven major electronic databases were searched from inception until October 2, 2017 to obtain relevant clinical variables to compare the difference in IGF-1 levels between delirious and non-delirious elderly in-patients. A random effects meta-analysis was conducted.ResultsWe studies 10 articles involving 294 delirious patients (mean age 73.0 years) and 604 non-delirious patients (mean age 76.9 years). We found that peripheral levels of IGF-1 in patients with delirium were significantly lower than in those without delirium (Hedges’ g = −0.209, 95% confidence interval [CI] = −0.393 to −0.026, p = 0.025). Meta-regression analyses found that no variables such as percentage of cognitive impairment, mean age, and female proportion contribute to heterogeneity in terms of the entire population.ConclusionsOur data suggests that lower peripheral levels of IGF-1 could be associated with a higher incidence of delirium among elderly patients. Further prospective studies with larger sample sizes are needed to investigate the association between peripheral levels of IGF-1 and delirium.     

IGF-1 and IGF-1BP3 in gastric adenocarcinoma. Preliminary study

BACKGROUND/AIMS: Insulin-like growth factor-1 (IGF-1) is a mitogenic and anti-apoptotic factor, mainly produced by the liver, which regulates cell proliferation. Most serum IGF-1s are bound with IGF-1BP3. Plasma IGF-1 values are positively related to cancer risk (breast, colon, and lung cancer) and seem to have a prognostic significance in prostatic cancer. The aim of this study is to investigate the relationship between IGF-1, IGF-1BP3 and gastric cancer. METHODOLOGY: IGF-1 and IGF-1BP3 serum levels were measured in 26 consecutive patients (M/F = 15/11, mean age 65 yrs) with histologically proven gastric adenocarcinoma from January 1999 to December 2000. Blood samples were collected at baseline, before surgery with radical intent (total and subtotal gastrectomies + D2 lymphadenectomy), and then at 14th and 50th postoperative days. These values were compared to a control group of healthy people. RESULTS: At baseline was observed a significant increase of IGF-1 serum levels in cancer patients versus control group (p < 0.001). All gastric cancer patients showed IGF-1 over normal limits. After surgery there was a significant decrease of IGF-1 levels (14th day vs. baseline, p = 0.001) that was still present in late postoperative period (50th day). At baseline IGF-1 values were not related to tumor extension or nodal involvement status. Otherwise in postoperative period IGF-1 significantly decreased in earlier stages (N0; T < or = 2) but not in more advanced ones (N+; T > 2). At baseline, IGF-1BP3 values were increased compared to control group but did not significantly decrease after surgery. CONCLUSIONS: IGF-1 values in gastric cancer patients are increased compared to control group, without stratification for stage and nodal status. Moreover radical surgery, with complete tumor ablation, induces a significant decrease in IGF-1 levels, without reach normal limits. Besides at baseline abnormally higher IGF-1BP3 values were observed, suggesting an alteration in IGF-1 and IGF-1BP3 system.     

Mesenchymal stem cells ameliorate impaired wound healing through enhancing keratinocyte functions in diabetic foot ulcerations on the plantar skin of rats

Aims/hypothesisAlthough the initial healing stage involves a re-epithelialization in humans, diabetic foot ulceration (DFU) has been investigated using rodent models with wounds on the thigh skin, in which a wound contraction is initiated. In this study, we established a rodent model of DFU on the plantar skin and evaluated the therapeutic efficacy of bone-marrow-derived mesenchymal stem cells (BM-MSCs) in this model.MethodsThe wounds made on the hind paws or thighs of streptozotocin induced diabetic or control rats were treated with BM-MSCs. Expression levels of phosphorylated focal adhesion kinase (pFAK), matrix metaroprotease (MMP)-2, EGF, and IGF-1, were evaluated in human keratinocytes, which were cultured in conditioned media of BM-MSCs (MSC-CM) with high glucose levels.ResultsRe-epithelialization initiated the healing process on the plantar, but not on the thigh, skin. The therapy utilizing BM-MSCs ameliorated the delayed healing in diabetic rats. In the keratinocytes cultured with MSC-CM, the decreased pFAK levels in the high glucose condition were restored, and the MMP2, EGF, and IGF-1 levels increased.Conclusions/interpretationOur study established a novel rat DFU model. The impaired healing process in diabetic rats was ameliorated by transplantation of BM-MSCs. This amelioration might be accounted for by the modification of keratinocyte functions.     

Possible roles of insulin,IGF-1 and IGFBPs in initiation and progression of colorectal cancer

AIM: To investigate the roles of serum insulin, insulinlike growth factor-1(IGF-1), and insulin-like growth factor binding proteins(IGFBPs) in the initiation and progression of colorectal cancer. METHODS: We determined serum insulin, IGF-1 and IGFBPs levels in 615 colorectal cancer patients and 650 control healthy donors by enzyme-linked immunosorbent assay(ELISA). In the meantime, their body mass index(BMI) and waist-to-hip ratio(WHR) were measured. RESULTS: Serum levels of insulin and IGF-1 as well as IGF-1/IGFBP-3 ratio in pre-operation patients were significantly elevated, but the level of IGFBP-3 was significantly decreased compared with normal controls and post-operation patients(P < 0.05 and P < 0.001,respectively). There is no significant difference(P > 0.05) in the levels of insulin, IGF-1, IGFBP-1, IGFBP-3 and IGF-1/IGFBP-3 between the patients with and without hepatic as well as distal abdominal metastases. WHR and BMI of colon cancer patients were positively and significantly correlated with the levels of insulin and IGF-1/IGFBP-3. In contrast, WHR and BMI were negatively correlated with IGFBP-3 level. CONCLUSION: The elevation of insulin, IGF-1 as well as IGF-1/IGFBP-3 ratio and the reduction of IGFBP-3 may be related to the initiation of colorectal cancer, but they are not related to the progression and outcome of the disease.     

Serum Levels of Fibroblast Growth Factor 19 Correlate with the Severity of Diarrhea and Independently from Intestinal Inflammation in Patients with Inflammatory Bowel Disease or Microscopic Colitis

BackgroundIn chronic diarrhea patients, massive over-reporting symptom-based criteria for functional bowel disorders are pitfalls. There is currently no objective biomarker that may provide a correct correlation with the severity of chronic diarrhea. To clarify the role of fibroblast growth factor-19 (FGF-19) as a biomarker of objective measurements of the severity of diarrhea in comparison with a patient-reported outcome, based on the Bristol Stool Form (BSF) Scale.MethodsConsecutive 100 patients with chronic diarrhea underwent standard investigations with laboratory tests, fecal calprotectin (FC), endoscopy with biopsies, and serum FGF-19. All patients and 14 healthy controls completed a diary recording, BSF, and stool frequency. ResultsWe found that irritable bowel syndrome with diarrhea (IBS-D) n = 21/23 (91%) reported a high number on BSF ≥6, compared to patients with inflammatory bowel diseases (IBD) 56/77 (72%) with BSF ≥ 6 (P = .011). FGF-19 median serum levels were significantly lower in Microscopic colitis (0.010 pg/mL) and IBD patients (0.009 pg/mL) compare to IBS-D (266.9 pg/mL) and high levels in healthy subjects (463 pg/mL) (P < .001). Strong inverse correlation of FGF-19 with the stool frequency/day and stool index was found (r = −0.800, P < .001; r = −0.739, P < .001), independently from disease activity (r = −0.718, P = .001; r = −0.792, P = .001).ConclusionSerum FGF-19 can become a new biomarker for evaluating the severity of diarrhea with objectively and independently from intestinal inflammation. FC and FGF-19 are predictive biomarkers for the organic cause of diarrhea.     

Insulin-like growth factor-1 (IGF-1) enhances developmental competence of cat embryos cultured singly by modulating the expression of its receptor (IGF-1R) and reducing developmental block

ObjectiveThe aim of this study is to determine the effects of insulin-like growth factor-1 (IGF-1) and the mRNA expression of IGF-1 receptor (IGF-1R) during the in vitro development of cat embryos cultured in groups versus singly.MethodsCumulus-oocyte complexes (COCs) were matured and fertilized in vitro with frozen-thawed semen. Cleaved embryos (48 h post-fertilization) were randomly assigned to one of the following treatments: 1) group embryo culture without IGF-1 (10 embryos per 50 μl droplet), 2) single-embryo culture without IGF-1, and 3) to 6) single-embryo culture (50 μl droplet per embryo) supplemented with different concentrations of IGF-1 (5, 25, 50 and 100 ng/ml, respectively). During in vitro culture, the embryos were analyzed for development to the morula, blastocyst and hatching blastocyst stage. Relative mRNA expression of IGF-1R was also examined by qPCR at the morula and blastocyst stages. In addition, the mRNA expression of IGF-1R in morula-stage embryos treated with IGF-1 was determined. The influence of IGF-1 to preimplantation embryo development was then explored by co-incubation with 0.5 μM IGF-1R inhibitor (Picropodophyllin; PPP).ResultsGroup embryo culture led to a significantly higher blastocyst development rate compared with single-embryo culture (P < 0.05). The poor development of singly cultured embryos coincided with the significantly lower IGF-1R expression in morulae than in group-cultured morulae. IGF-1 (25 or 50 ng/ml) supplementation significantly improved the blastocyst formation rate of single embryos to a level similar to group culture by promoting the morula-to-blastocyst transition. IGF-1 supplementation (25 or 50 ng/ml) of singly cultured embryos upregulated the expression of IGF-1R mRNA in morula-stage embryos to the same level as that observed in group-cultured embryos (without IGF-1). The beneficial effects of IGF-1 on singly cultured embryo were (P < 0.05) suppressed by PPP even in the group culture embryo without growth factor supplementation.ConclusionIGF-1 supplementation improves the developmental competence of feline embryos cultured individually and also increases IGF-1R gene expression to levels similar to group-cultured embryos.     

Hyperglycemia is associated with lower levels of urokinase-type plasminogen activator and urokinase-type plasminogen activator receptor in wound fluid

AimsWounds in patients with hyperglycemia show impaired healing. Plasminogen activation is crucial in several overlapping phases of wound healing process. In this study, we aimed i) to compare acute wound fluid in patients with hyperglycemia and normoglycemia, ii) to focus on the elements of plasminogen activation in the wound fluid, and iii) to determine if the acute wound fluid characteristics are associated with surgical site infections.MethodsIn a cohort of 54 patients, a closed suction drain was placed in the wound above the anterior abdominal wall fascia under the skin in order to collect postoperative acute wound fluid samples for 3 following days after colorectal surgery. Patients were classified as normoglycemic (n = 25) or hyperglycemic (n = 29; 17 with type 2 diabetes and 12 with stress induced hyperglycemia). Surgical site infection was defined according to the Centers for Disease Control criteria. The levels of urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAr), plasminogen activator inhibitor-1 (PAI-1), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and fibroblast growth factor-1 (FGF-1) were measured in the wound fluid.ResultsCompared to normoglycemic subjects, patients with hyperglycemia had significantly lower levels of uPA and uPAr in the wound fluid despite similar or even higher circulating levels. There was no significant difference in IL-1β, TNF-α, PAI-1 and FGF-1 levels. In the whole study population, the wound fluid levels of uPA and uPAr were negatively correlated with circulating glucose levels. No difference was detected in the wound fluid characteristics of patients with and without surgical site infection.ConclusionPatients with hyperglycemia exhibit decreased levels of uPA and uPAr in the wound fluid, suggesting a local failure in plasminogen activation at the wound site.     

Differential effects of IGF-1 deficiency during the life span on structural and biomechanical properties in the tibia of aged mice

Advanced aging is associated with the loss of structural and biomechanical properties in bones, which increases the risk for bone fracture. Aging is also associated with reductions in circulating levels of the anabolic signaling hormone, insulin-like growth factor (IGF)-1. While the role of IGF-1 in bone development has been well characterized, the impact of the age-related loss of IGF-1 on bone aging remains controversial. Here, we describe the effects of reducing IGF-1 at multiple time points in the mouse life span—early in postnatal development, early adulthood, or late adulthood on tibia bone aging in both male and female igf ^f/f mice. Bone structure was analyzed at 27 months of age using microCT. We find that age-related reductions in cortical bone fraction, cortical thickness, and tissue mineral density were more pronounced when IGF-1 was reduced early in life and not in late adulthood. Three-point bone bending assays revealed that IGF-1 deficiency early in life resulted in reduced maximum force, maximum bending moment, and bone stiffness in aged males and females. The effects of IGF-1 on bone aging are microenvironment specific, as early-life loss of IGF-1 resulted in decreased cortical bone structure and strength along the diaphysis while significantly increasing trabecular bone fraction and trabecular number at the proximal metaphysis. The increases in trabecular bone were limited to males, as early-life loss of IGF-1 did not alter bone fraction or number in females. Together, our data suggest that the age-related loss of IGF-1 influences tibia bone aging in a sex-specific, microenvironment-specific, and time-dependent manner.     

Serum EGF and NGF levels of patients with brain injury and limb fracture

ObjectiveTo explore the expression and significance of human epidermal growth factor (EGF) and nerve growth factor (NGF) in patients with knee osteoarthritis.MethodsRT-PCR and enzyme-linked immunosorbent assay were used to measure the serum EGF and NGF expression levels of patients with limb fracture and brain trauma injurry after 1 d, 3 d, 7 d, 14 d and the relationship between them was analyzed. The level was compared among the simple fracture group, traumatic brain injury group and the normal control group, with 40 cases in each group.ResultsThe serum NGF levels were significantly different among three groups. Serum NGF, EGF mRNA and protein levels gradually decreased with the increasing injury time in the limb fracture combined with brain injury group, traumatic brain injury group, the simple fracture group and the health control group (P<0.05).ConclusionsThe serum of NGF, EGF levels significantly increased when limb fracture combined with brain injury, so EGF and NGF may be involved in the process of fracture healing.     

Low circulating insulin-like growth factor-1 levels are associated with high serum uric acid in nondiabetic adult subjects

Background and aimsLow insulin-like growth factor-1 (IGF-1) levels and high uric acid concentrations are associated with cardio-metabolic disorders. Acute IGF-1 infusion decreases uric acid concentration in healthy individuals. In this study, we aimed to examine the relationship between IGF-1 and uric acid levels.Methods and results1430 adult non diabetic subjects were stratified into quartiles according to their circulating IGF-1 values. Significant differences in uric acid concentration, measured by the URICASE/POD method were observed between low (quartile 1), intermediate (quartile 2 and 3), and high (quartile 4) IGF-1 levels groups after adjusting for age, gender, and body mass index (P = 0.02). These differences remained significant after adjustment for blood pressure, total cholesterol, high density lipoprotein, triglycerides, fasting and 2 h post-load glucose levels, HOMA-IR index (P = 0.005), liver enzymes (P = 0.03), glucose tolerance status (P = 0.02), growth hormone levels (GH) (P = 0.05), anti-hypertensive treatments (P = 0.04) or diuretics use (P = 0.04)). To clarify the molecular links between IGF-1 and uric acid, we performed an in vitro study, incubating human hepatoma cells with uric acid for 24 or 48 h in the presence of GH and observed a 21% and 26% decrease, respectively, in GH-stimulated IGF-1 mRNA expression (P = 0.02 and P = 0.012, respectively). This effect appears to be mediated by uric acid ability to down regulate GH intracellular signaling; in fact we observed a significant decrease of GH activated JAK2 and Stat5 phosphorylation.ConclusionsThese data demonstrate an inverse relationship between IGF-1 and uric acid levels in adults and suggest that uric acid might affect hepatic IGF-1 synthesis.