Activation of Peroxisome Proliferator-Activated Receptor γ (PPARγ) by Rosiglitazone Suppresses Components of the Insulin-Like Growth Factor Regulatory System in Vitro and in Vivo

• Published in: Endocrinology (Philadelphia) Vol. 148; no. 2; pp. 903 - 911
• Main Authors: Lecka-Czernik, B., Ackert-Bicknell, C., Adamo, M. L., Marmolejos, V., Churchill, G. A., Shockley, K. R., Reid, I. R., Grey, A., Rosen, C. J.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.02.2007; Oxford University Press
• Subjects: Adipogenesis; Adipose Tissue - metabolism; Animals; Biological and medical sciences; Bone growth; Bone Marrow Cells - metabolism; C cells; Cell Line; Down-Regulation; Drug Administration Schedule; Female; Fundamental and applied biological sciences. Psychology; Growth factors; Humans; Insulin-Like Growth Factor Binding Protein 2 - blood; Insulin-Like Growth Factor Binding Protein 3 - blood; Insulin-Like Growth Factor Binding Protein 4 - antagonists & inhibitors; Insulin-Like Growth Factor Binding Protein 4 - genetics; Insulin-like growth factor I; Insulin-Like Growth Factor I - antagonists & inhibitors; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor I - secretion; Insulin-like growth factor II; Insulin-Like Growth Factor II - antagonists & inhibitors; Insulin-Like Growth Factor II - metabolism; Insulin-like growth factor II receptors; Insulin-like growth factor-binding protein 2; Insulin-like growth factor-binding protein 3; Insulin-like growth factor-binding protein 4; Insulin-like growth factors; Liver; Liver - cytology; Liver - metabolism; Mice; Mice, Inbred C57BL; Microarray Analysis; Osteoblasts - physiology; Osteogenesis; Ovariectomy; Paracrine signalling; Peroxisome proliferator-activated receptors; Placebos; Post-menopause; PPAR gamma - drug effects; PPAR gamma - genetics; PPAR gamma - metabolism; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, IGF Type 1 - genetics; Receptors; RNA, Messenger - metabolism; Rosiglitazone; Somatomedins - metabolism; Stromal cells; Stromal Cells - drug effects; Stromal Cells - metabolism; Thiazolidinediones; Thiazolidinediones - administration & dosage; Thiazolidinediones - pharmacology; Transfection; Vertebrates: endocrinology; In vivo; Insulin like growth factor; Rosiglitazone; Thiazolidinedione derivatives; Activation; PPAR-γ receptor; In vitro
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2006-1121

Rosiglitazone (Rosi) belongs to the class of thiazolidinediones (TZDs) that are ligands for peroxisome proliferator-activated receptor γ (PPARγ). Stimulation of PPARγ suppresses bone formation and enhances marrow adipogenesis. We hypothesized that activation of PPARγ down-regulates components of the IGF regulatory system, leading to impaired osteoblast function. Rosi treatment (1 μm) of a marrow stromal cell line (UAMS-33) transfected with empty vector (U-33/c) or with PPARγ2 (U-33/γ2) 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/γ2 compared with U-33/c cells (P < 0.01); these findings were confirmed by RT-PCR. Rosi reduced secreted IGF-I from U-33/γ2 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 μm) 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.