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Endocrinology, doi:10.1210/en.2003-0746
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Endocrinology Vol. 145, No. 1 401-406
Copyright © 2004 by The Endocrine Society

Bone Is a Target for the Antidiabetic Compound Rosiglitazone

S. O. Rzonca, L. J. Suva, D. Gaddy, D. C. Montague and B. Lecka-Czernik

Department of Geriatrics, Reynolds Center on Aging (S.O.R., B.L.-C.), Department of Orthopaedic Surgery, Center for Orthopaedic Research (L.J.S., D.G., D.C.M.), and Department of Physiology and Biophysics (L.J.S., D.G, D.C.M.), University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

Address all correspondence and requests for reprints to: Beata Lecka-Czernik, Department of Geriatrics, Reynolds Center on Aging, University of Arkansas for Medical Sciences, 629 South Elm Street, Little Rock, Arkansas 72205. E-mail: BLecka-Czernik{at}uams.edu.

Rosiglitazone is an FDA-approved oral antidiabetic agent for the treatment of type 2 diabetes. This compound improves insulin sensitivity through the activation of the nuclear receptor, peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}). In addition to sensitizing cells to insulin, the PPAR-{gamma}2 isoform appears to be critical for the regulation of osteoblast and adipocyte differentiation from common mesenchymal bone marrow progenitors. We have demonstrated previously that PPAR-{gamma}2 activated with rosiglitazone acts as a dominant inhibitor of osteoblastogenesis in murine bone marrow in vitro. Here, we show that in vivo, rosiglitazone administration results in significant bone loss. When rosiglitazone (20 µg/g body weight/d) was given to 6-month-old, nondiabetic C57BL/6 mice for 7 wk, a significant decrease in total body bone mineral density was observed. Analysis of bone microarchitecture, using micro-computed tomography, demonstrated a decrease in bone volume, trabecular width, and trabecular number and an increase in trabecular spacing. Histomorphometric analysis showed a decrease in bone formation rate, with a simultaneous increase in fat content in the bone marrow. Changes in bone morphology and structure were accompanied by changes in the expression of osteoblast- and adipocyte- specific marker genes; the expression of the osteoblast-specific genes Runx2/Cbfa1, Dlx5, and {alpha}1(I)collagen were decreased, whereas the expression of the adipocyte-specific fatty acid binding protein aP2, was increased. These in vivo data suggest that rosiglitazone therapy may pose a significant risk of adverse skeletal effects in humans.




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