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Submitted on August 15, 2006
Accepted on November 3, 2006
University of Arkansas for Medical Sciences Department of Geriatrics, Little Rock AR; The Jackson Laboratory, Bar Harbor ME; University of Texas San Antonio Health Sciences Center; and University of Auckland, Auckland NZ
* To whom correspondence should be addressed. E-mail: rofe{at}aol.com.
Rosiglitazone (Rosi) belongs to the class of thiazolidinediones (TZDs) that are ligands for peroxisome proliferator-activated receptor gammaa (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 (OB) function. Rosi treatment (1 µM) of a marrow stromal cell line (UAMS-33) transfected with empty vector (U-33/c) or with PPARgamma2 (U-33/
2) were analyzed by micro-array. Rosi reduced IGF-I, IGF-II, IGFBP-4, and the type I and type 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 mo) and old (24 mo) 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 days), and long term (i.e. 7 weeks) 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 if Rosi affected circulating IGF-I in humans, we measured serum IGF-I, IGFBP-2 and IGFBP-3 at 4 times points in 50 postmenopausal women randomized to either Rosi (8 mg/d) or placebo. Rosi treated subjects had significantly lower IGF-I at 8 weeks than baseline (-25%, P < 0.05), and at 16 weeks 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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