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

University of Arkansas for Medical Sciences Department of Geriatrics (B.L.-C.), Little Rock, Arkansas; The Jackson Laboratory (C.A.-B., V.M., G.A.C., K.R.S., C.J.R.), Bar Harbor, Maine; University of Texas, San Antonio, Health Sciences Center (M.L.A.), San Antonio, Texas; and University of Auckland (I.R.R., A.G.), Auckland, New Zealand

Address all correspondence and requests for reprints to: Clifford J. Rosen, M.D., St. Joseph Hospital, Maine Center for Osteoporosis Research and Education, 360 Broadway, Bangor, Maine 04401. E-mail: rofe{at}aol.com.

Rosiglitazone (Rosi) belongs to the class of thiazolidinediones (TZDs) that are ligands for peroxisome proliferator-activated receptor (PPAR). Stimulation of PPAR suppresses bone formation and enhances marrow adipogenesis. We hypothesized that activation of PPAR 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 PPAR2 (U-33/2) 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-33/2 compared with U-33/c cells (P < 0.01); these findings were confirmed by RT-PCR. Rosi reduced secreted IGF-I from U-33/2 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.

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