T. Chevalley et al., ARGININE INCREASES INSULIN-LIKE GROWTH-FACTOR-I PRODUCTION AND COLLAGEN-SYNTHESIS IN OSTEOBLAST-LIKE CELLS, Bone (New York, N.Y.), 23(2), 1998, pp. 103-109
Protein-energy malnutrition, which is common in elder-ly patients with
osteoporotic hip fractures, is associated with reduced plasma revels
of insulin-like growth factor-I (IGF-I), IGF-I is an important regulat
or of bone metabolism, particularly of osteoblastic hone formation bot
h in vivo and in vitro. Pharmacological doses of arginine (Arg) increa
se growth hormone (GH) and IGF-I serum levels. Whether amino acids, pa
rticularly Arg, can directly modulate the production of IGF-I by osteo
blasts is not known. We investigated the effects of increasing concent
rations of Arg on IGF-I expression and production, alpha(1)(I) collage
n expression and collagen synthesis, and cell proliferation and cell d
ifferentiation, as assessed by alkaline phosphatase (ALP) activity and
osteocalcin (OC) release, in confluent mouse osteoblastlike MC3T3-E1
cells. The addition of Arg (7.5-7500 mu mol/L, equivalent to 0.1- to 1
00-fold human plasma concentration! for 48 h increased IGF-I productio
n (adjusted for cell number) in a concentration-dependent manner with
a maximum of 2.3 +/- 0.3-fold at 7500 mu mol/L Arg [x +/- standard err
or of the mean (SEM), n = 3 experiments, p < 0.01]. Arg (7.5-7500 mu m
ol/L) increased the percentage of de novo collagen synthesis in a conc
entration-dependent manner (2.1 +/- 0. 4-fold with 7500 mu mol/L Arg,
p < 0.001) and ALP activity with a maximal stimulation of 144% +/- 13%
plateauing at 750 mu mol/L Arg (p = 0.001). The steady state level of
IGF-I messenger ribonucleic acid (mRNA) and alpha(1)(I) collagen mRNA
(both normalized to cyclophilin mRNA) of cells incubated with Arg at
high (100-fold) or low (0.1-fold) human plasma concentrations, was 1.4
+/- 0.2, 1.2 +/- 0.2, and 1.1 +/- 0.2 after 24 h for the 7.5, 1.8, an
d 0.9 kb IGF-I mRNA transcripts, respectively (n = 3 experiments) and
1.5 +/- 0.2 and 3.1 +/- 0.7 after 24 and 48 h, respectively, for the c
ombined analysis of the 5.6 and 4.7 kb alpha(1)(I) collagen mRNA trans
cripts (n = 3 experiments). A maximal mitogenic effect (cell number) o
f +21% +/- 3% (p < 0.01) was obtained with 1000 mu mol/L Arg, In contr
ast, Arg (7.5-7500 mu mol/L) induced a reduction of OC production, whi
ch reached 30% +/- 3% with 7500 mu mol/L Arg (p = 0.02), In conclusion
, Arg stimulated IGF-I production and collagen synthesis in osteoblast
-like cells. Thus, Arg may influence bone formation by enhancing local
IGF-I production. (Bone 23:103-109; 1998) (C) 1998 by Elsevier Scienc
e Inc. All rights reserved.