The IGF system in patients with inflammatory bowel disease treated with prednisolone or infliximab: potential role of the stanniocalcin-2 / PAPP-A / IGFBP-4 axis.

BACKGROUND: Patients with inflammatory bowel disease (IBD) present with reduced serum insulin-like growth factor I (IGF-I). Anti-inflammatory treatment with prednisolone or infliximab ameliorates symptoms and increases circulating IGF-I, but prednisolone induces catabolism, whereas infliximab may promote protein synthesis. Recently, stanniocalcin-2 (STC2) was discovered as a novel inhibitor of the enzyme pregnancy-associated plasma protein-A (PAPP-A), which modulates IGF-I activity. PAPP-A can cleave IGF binding protein-4 (IGFBP-4), upon which IGF-I is liberated. We hypothesized that prednisolone and infliximab exert different effects on levels of STC2, PAPP-A, and IGFBP-4, thereby explaining the distinct metabolic effects of prednisolone and infliximab. METHODS: Thirty-eight patients with active IBD treated with either prednisolone (n = 17) or infliximab (n = 21) were examined before and after 7 days of treatment. Circulating levels of IGF-I, IGF-II, IGFBP-3, PAPP-A, and STC2 were measured by immunoassays. Intact IGFBP-4 and two IGFBP-4 fragments were determined by a novel immunoassay. Bioactive IGF was assessed by cell-based IGF receptor activation assay. Concentrations of IGFBP-4, PAPP-A, and STC2 on day 0 and 7 were compared to healthy control subjects. RESULTS: Following seven days of prednisolone treatment, total and bioactive IGF-I were increased (p < 0.001 and p < 0.05, respectively). Upon infliximab treatment, total IGF-I levels were augmented (p < 0.05), yet IGF bioactivity remained unaltered. Intact IGFBP-4 and the two IGFBP-4 fragments generated upon cleavage by PAPP-A were all decreased following treatment with either prednisolone or infliximab (all p < 0.05). PAPP-A levels were only increased by infliximab (p = 0.005), whereas the inhibitor STC2 did not respond to any of the treatments. CONCLUSION: IGF-I and IGFBP-4 concentrations were markedly altered in patients with IBD and near-normalized with disease remission following treatment with prednisolone or infliximab. Thus, IGFBP-4 may modulate IGF bioavailability in IBD. The effect of immunosuppression did not appear to extend beyond the regulation of IGF and IGFBP-4, as neither PAPP-A nor STC2 were discernibly affected. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00955123 . Date of registration: August 7, 2009 (retrospectively registered).

Pregnancy-associated plasma protein-A (PAPP-A) levels in patients with severe allergic asthma are reduced by omalizumab.

BACKGROUND: Remodeling is a crucial feature of severe asthma and may be associated with activation of the allergic cascade by immunoglobulin E (IgE). Omalizumab, an anti-IgE monoclonal antibody, effectively targets the severe allergic asthma phenotype. Pregnancy-associated plasma protein-A (PAPP-A) is an insulin-like growth factor binding protein-4 (IGFBP-4) protease, increasing local insulin-like growth factor (IGF)-1 concentrations, which in turn initiating a cascade involved in the regulation of cell growth, differentiation, and proliferation in various tissues. In the present study, we evaluated the effects of omalizumab on serum PAPP-A, IGFBP-4, and IGF-1 levels in subjects with severe allergic asthma. METHODS: We studied 36 asthmatic subjects and 36 healthy controls. An ultrasensitive enzyme-linked immunosorbent assay (ELISA) kit was used to measure serum PAPP-A levels, and routine commercial ELISA kits were employed to assess serum levels of IGF-1, IGFBP-4 in control subjects and asthmatic subjects before therapy (baseline) and after six months of omalizumab therapy in patients with severe asthma. RESULTS: Compared to control subjects, serum PAPP-A and IGFB-4 levels were significantly higher in asthmatic subjects (both p values < 0.001). However, the serum IGF-I levels of asthmatic subjects were similar to those of control subjects (p > 0.05). In asthma subjects, 6-month omalizumab treatment significantly decreased the serum PAPP-A (p < 0.001), IGF-I (p = 0.031), and IGFB4 (p = 0.025) levels. CONCLUSION: PAPP-A level may be a useful biomarker for predicting airway remodeling in patients with severe asthma receiving omalizumab, and may also reflect the response to treatment.

Effect of smoke on PAPP-A and lipid profile in normal rats.

Cigarette smoking is a major risk factor for atherosclerosis and cardiovascular disease. Active and passive cigarette smoke exposure predisposes to cardiovascular events. Pregnancy associated plasma protein-A is a metalloproteinase of the metzincin super family. It cleaves specific insulin like growth factor binding proteins thereby regulating local insulin like growth factor bioavailability which is a mediator of atherosclerosis. In this study we wanted to establish if Pregnancy associated plasma protein-A levels are increased in normal rats and if the Lipid profile was affected, if exposed to passive smoking. Sixty albino rats of Sprague-Dawley strain were used, weighing 200-250 gm. Both the groups were kept in identical chambers. One group of 30 rats was further exposed to cigarette smoke. Blood triglycerides were determined by enzymatic colorimetric method. In this animal study it was seen that smoking had no effect on (triglycesides), cholesterol, LDL and HDL levels. Smoke exposure has no effect on pregnancy associated plasma protein-A (PAPP-A) levels.

Transforming growth factor-beta regulation of the insulin-like growth factor binding protein-4 protease system in cultured human osteoblasts.

IGFBP-4 is an inhibitor of IGF-I in bone. We show that TGF-beta regulates IGFBP-4 and enhances IGF-I-stimulated growth of cultured human bone cells through increased expression of an IGFBP-4 protease, PAPP-A. This effect of TGF-beta on IGF-I bioavailability may promote local bone formation. Insulin-like growth factor binding protein (IGFBP-4) proteolysis is implicated in the regulation of local insulin-like growth factor (IGF)-I bioavailability during bone remodeling. The IGFBP-4 protease secreted by normal adult human osteoblastic (hOB) cells in culture is a novel metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A). We have recently identified an inhibitor of PAPP-A, the precursor form of major basic protein (proMBP). Very little is known about the molecular regulation of this IGFBP-4 protease system. In the present study, we determined the effect of transforming growth factor (TGF)-beta and IGF-II, the two most abundant growth factors in human bone, on PAPP-A and proMBP expression in primary cultures of hOB cells. Treatment with TGF-beta resulted in time- and dose-dependent increases in PAPP-A mRNA expression, with a maximal 12-fold increase after 24 h of stimulation with 10 ng/ml TGF-beta. Increased PAPP-A levels in hOB cell-conditioned medium paralleled PAPP-A gene expression. In addition, TGF-beta completely suppressed proMBP expression. Treatment of hOB cells with IGF-II had no effect on PAPP-A or proMBP gene expression. However, IGFBP-4 proteolysis in cell-free assay was dependent on IGF-II, and there was increased IGF-II-dependent IGFBP-4 protease activity in conditioned medium from hOB cells that were treated with TGF-beta. IGF-I stimulation of hOB cell proliferation was markedly enhanced by pretreatment with TGF-beta and [Leu27]IGF-II, and this enhancement was prevented with protease-resistant IGFBP-4. In summary, TGF-beta regulates IGFBP-4 proteolysis in hOB cells through increased expression of the protease, PAPP-A, and decreased expression of the inhibitor, proMBP. However, functional activation of the IGFBP-4 protease system is dependent on IGF-II, which acts at a post-translational level. These data support a model whereby local TGF-beta and IGF-II in the bone microenvironment coordinately amplify IGF-I bioavailability through controlled IGFBP-4 proteolysis, which may be a means to promote bone formation.

Long-term influence of diet and/or omega-3 fatty acids on matrix metalloproteinase-9 and pregnancy-associated plasma protein-A in men at high risk of coronary heart disease.

BACKGROUND: Matrix metalloproteinases (MMPs) are important in the atherosclerotic process. The relationship between MMPs and traditional risk factors for cardiovascular disease (CVD) and any influence of lifestyle changes are largely unknown. OBJECTIVES: In a factorial design, we studied the effects of 3 years of dietary counselling and/or n-3 PUFA supplementation (2.4 g/d) on the levels of MMP-9, tissue inhibitor of metalloproteinase (TIMP-1) and pregnancy-associated plasma protein (PAPP-A) in a population of elderly men at high risk of CVD (n = 563, age 70+/-6 years). We further explored the association between these markers and different disease entities, carotid intima media thickness (IMT) and traditional risk factors for CVD. RESULTS: Smokers had significantly higher levels of MMP-9 (p<0.0001), and TIMP-1 levels were lower in subjects with previous AMI (p = 0.021). MMP-9 was significantly correlated with LDL-C and inversely with HDL-C (both p<0.0001). There were no significant correlations between the measured variables and IMT. Significant reductions in MMP-9 and PAPP-A levels after 36 months were found in all study groups, however, with no between-group differences. CONCLUSIONS: The elevated levels of MMP-9 in smokers and the reduced levels of TIMP-1 in patients with previous AMI reflect an importance of MMPs in the development of CVD. Intervention with diet and/or n-3 PUFA supplementation did not influence the levels of MMP-9, TIMP-1 or PAPP-A in the present population.

Intravenous iron gluconate administration increases circulating PAPP-A in hemodialysis patients.

BACKGROUND: Pregnancy-associated plasma protein-A (PAPP-A) is a proatherosclerotic molecule, interrelated with oxidative stress in hemodialysis (HD) patients. As intravenous (IV) iron might enhance oxidative stress in HD patients, this study investigates circulating PAPP-A during HD session and after IV iron administration. METHODS: In 20 HD patients, plasma PAPP-A concentration was assessed immunochemically during 2 HD sessions (prior to HD and at 60, 130, and 240 min of HD session). Sodium ferric gluconate (62.5 mg) was given IV to all patients 65 min after the start of the second HD. RESULTS: Sixty-five min after IV iron application, there was a significant increase in plasma PAPP-A (from 36.0+/-9.9 to 79.6+/-28.9 mU/L, p<0.0001). At the end of this HD session, PAPP-A decreased significantly (p<0.0001), but still remained 1.5-fold greater compared with predialysis levels (p<0.0005). CONCLUSION: IV iron increases circulating PAPP-A, and in this way, it might contribute to more pronounced cardiovascular complications in HD patients.