Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by rosiglitazone suppresses components of the insulin-like growth factor regulatory system in vitro and in vivo.
Document Type
Article
Publication Date
2007
Keywords
Animals, Bone-Marrow-Cells, Cell-Line, Down-Regulation, Drug-Administration-Schedule, Female, Humans, Insulin-Like-Growth-Factor-Binding-Protein-2, Insulin-Like-Growth-Factor-Binding-Protein-3, Insulin-Like-Growth-Factor-Binding-Protein-4, Insulin-Like-Growth-Factor-I, Insulin-Like-Growth-Factor-II, Liver, Mice-Inbred-C57BL, Microarray-Analysis, Osteoblasts, Ovariectomy, PPAR-gamma, RNA-Messenger, Receptor-IGF-Type-1, Somatomedins, Stromal-Cells, Thiazolidinediones, Transfection
First Page
903
Last Page
911
JAX Source
Endocrinology 2007 Feb; 148(2):903-11.
Abstract
Rosiglitazone (Rosi) belongs to the class of thiazolidinediones (TZDs) that are ligands for peroxisome proliferator-activated receptor gamma (PPARgamma). Stimulation of PPARgamma suppresses bone formation and enhances marrow adipogenesis. We hypothesized that activation of PPARgamma down-regulates components of the IGF regulatory system, leading to impaired osteoblast function. Rosi treatment (1 microm) of a marrow stromal cell line (UAMS-33) transfected with empty vector (U-33/c) or with PPARgamma2 (U-33/gamma2) were analyzed by microarray. Rosi reduced IGF-I, IGF-II, IGFBP-4, and the type I and II IGF receptor (IGF1R and IGF2R) expression at 72 h in U-33/gamma2 compared with U-33/c cells (P < 0.01); these findings were confirmed by RT-PCR. Rosi reduced secreted IGF-I from U-33/gamma2 cells by 75% (P < 0.05). Primary marrow stromal cells (MSCs) extracted from adult (8 months) and old (24 months) C57BL/6J (B6) mice were treated with Rosi (1 microm) for 48 h. IGF-I, IGFBP-4, and IGF1R transcripts were reduced in Rosi-treated MSCs compared with vehicle (P < 0.01) and secreted IGF-I was also suppressed (P < 0.05). B6 mice treated with Rosi (20 mg/kg.d) for short duration (i.e. 4 d), and long term (i.e. 7 wk) had reduced serum IGF-I; this was accompanied by markedly suppressed IGF-I transcripts in the liver and peripheral fat of treated animals. To determine whether Rosi affected circulating IGF-I in humans, we measured serum IGF-I, IGFBP-2, and IGFBP-3 at four time points in 50 postmenopausal women randomized to either Rosi (8 mg/d) or placebo. Rosi-treated subjects had significantly lower IGF-I at 8 wk than baseline (-25%, P < 0.05), and at 16 wk their levels were reduced 14% vs. placebo (P = 0.15). We conclude that Rosi suppresses IGF-I expression in bone and liver; these changes could affect skeletal acquisition through endocrine and paracrine pathways.
Recommended Citation
Lecka CB,
Ackert BC,
Adamo ML,
Marmolejos V,
Churchill GA,
Shockley KR,
Reid IR,
Grey A,
Rosen CJ.
Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by rosiglitazone suppresses components of the insulin-like growth factor regulatory system in vitro and in vivo. Endocrinology 2007 Feb; 148(2):903-11.