Androgen induction of steroid 5 alpha-reductase may be mediated via insulin-like growth factor-I.
Horton R,
Pasupuletti V,
Antonipillai I.
Source
Department of Medicine, University of Southern California School of Medicine, Los Angeles 90033.
Abstract
The action of added insulin-like growth factor-I (IGF-I) and dihydrotestosterone (DHT) on steroid 5 alpha-reductase (5 alpha R) activity was studied using primary cultures of rat or human scrotal skin fibroblasts. Agents were added to cultured cells (2 x 10(5) cells) for 2 days, and enzyme activity was measured by the percent conversion of [3H] testosterone to DHT over a 4-h period in the absence of fetal calf serum or other growth factors. DHT, but not testosterone, at 10(-7) M significantly increased 5 alpha R activity (rat, 1.5 +/- 0.3% to 3.0 +/- 0.4%; human, 7.6 +/- 1.7% to 11.4 +/- 2.9%; P < 0.01). IGF-I (10(-9)-6.4 x 10(-9) M), but not IGF-II (10(-9)-10(-8) M) or insulin (10(-9)-10(-7) M), increased enzyme activity in a dose-related fashion [i.e. 1.5 +/- 0.5 to 10 +/- 2 in rat and 6.0 +/- 1.1 to 9.8 +/- 1.6% (P < 0.01) in human cells]. No change in cell numbers was observed in any experiment. Since the effect of IGF-I was about 100 times that of androgen, we studied the possibility that androgen induction of the enzyme activity could be via IGF-I production. Addition of a monoclonal antibody against IGF-I significantly reduced the effect of DHT, and simultaneous addition of a specific IGF-I receptor antibody blocked the expected induction of 5 alpha R activity (control, 4.9 +/- 0.5; DHT, 8.0 +/- 1.9; DHT plus IGF-I receptor antibody, 3.7 +/- 0.4%). No effect on 3 alpha-reduction of [3H]DHT to 3 alpha-androstanediol was detected in separate experiments.
These studies indicate that IGF-I may be an important regulator of skin 5 alpha R activity and, thus, may influence DHT formation. The previously known androgen induction of this peripheral steroidogenic enzyme may be via paracrine/autocrine production of an IGF-I-type growth factor.
[h=1]Amelioration of excess collagen IαI, fibrosis, and smooth muscle growth in TNBS-induced colitis in IGF-I(+/-) mice.[/h]
Mahavadi S,
Flynn RS,
Grider JR,
Qiao LY,
Murthy KS,
Hazelgrove KB,
Kuemmerle JF.
[h=3]Source[/h]Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298-0341, USA.
[h=3]Abstract[/h][h=4]BACKGROUND:[/h]Strictures occur in ≈ 30% of patients with Crohn's disease (CD) and are characterized by intestinal smooth muscle hyperplasia, hypertrophy, and fibrosis due to excess extracellular matrix production including collagen. Insulin-like growth factor-I (IGF-I) expression is increased in smooth muscle cells of the muscularis propria in CD and in animal models of CD, including trinitrobenzene sulfonic acid (TNBS)-induced colitis. While upregulated IGF-I is conjectured to cause smooth muscle cell growth and collagen production in the inflamed intestine, its role in the development of fibrosis has not been directly demonstrated.
[h=4]METHODS:[/h]Colitis was induced in IGF-I(+/-) or wildtype C57BL/6J mice by rectal administration of TNBS or ethanol vehicle. After 7 days, colonic smooth muscle cells were isolated and used to prepare RNA or protein lysates. Transcript levels of IGF-IEa, IGF binding protein (IGFBP)-3, IGFBP-5, TGF-β1, and collagen IαI were measured by quantitative reverse-transcription polymerase chain reaction (RT-PCR). Corresponding protein levels were measured by Western blot or enzyme-linked immunosorbent assay (ELISA). Fibrosis was measured using digital image analysis of Masson's trichrome-stained histologic sections.
[h=4]RESULTS:[/h]In IGF-I(+/-) mice, which express significantly lower levels of IGF-I than wildtype, the response to TNBS-induced colitis: upregulation of IGF-I, IGFBP-3, IGFBP-5 muscle growth, and collagen IαI expression, the resulting collagen deposition, and fibrosis are all significantly diminished compared to C57BL/6J wildtype controls. TGF-β1 expression and its increase following TNBS administration are not altered in IGF-I(+/-) mice compared to wildtype.
[h=4]CONCLUSIONS:[/h]
The findings indicate that IGF-I is a key regulator in intestinal smooth muscle hyperplasia and excess collagen production that leads to fibrosis and long term to stricture formation.
