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

Rikke Hjortebjerg, Karen L Thomsen, Jørgen Agnholt, Jan Frystyk, Rikke Hjortebjerg, Karen L Thomsen, Jørgen Agnholt, Jan Frystyk

Abstract

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).

Keywords: IGF binding protein-4; Inflammatory bowel disease; Infliximab; Prednisolone; Pregnancy-associated plasma protein-a; Stanniocalcin-2.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The stanniocalcin-2/PAPP-A/IGFBP-4 axis. Left: PAPP-A cleaves IGFBP-4 into two fragments in the vicinity of the IGF-IR, resulting in liberation of bioactive IGF that can activate its receptor. Right: stanniocalcin-2 inhibits PAPP-A degradation of IGFBP-4, resulting in decreased levels of bioactive IGF and consequently reduced IGF signaling. IGF, insulin-like growth factor; IGF-IR, IGF-I receptor; IGFBP, IGF binding protein; PAPP-A, pregnancy-associated plasma protein-A; STC2, Stanniocalcin-2
Fig. 2
Fig. 2
Line plots illustrating individual changes in IGF system protein levels from day 0 to day 7 after treatment with prednisolone or infliximab. The individual changes in total IGF-I, IGF-II, bioactive IGF, IGFBP-3, IGFBP-4, NT-IGFBP-4, CT-IGFBP-4, PAPP-A, and STC2 before and after 7 days of prednisolone or infliximab. Solid lines illustrate patients, in which protein levels were increased following therapy, whereas dashed lines show patients that had lowered protein levels. Red diamonds illustrate mean or median protein level before and after treatment. CT, C-terminal; IGF, insulin-like growth factor; IGFBP, IGF binding protein; NS, not significant; NT, N-terminal; PAPP-A, pregnancy-associated plasma protein-A; STC2, Stanniocalcin-2

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