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Stimulation of Resorption in Cultured Mouse Calvarial Bones by Thiazolidinediones

Department of Physiology and Biophysics (A.M.S., B.W., H.H.C.), University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205; and Department of Oral Cell Biology (S.G., E.P., U.H.L.), Umeå University, SE-901 87 Umeå, Sweden

Address all correspondence and requests for reprints to: Howard H. Conaway, Ph.D., Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 505, Little Rock, Arkansas 72205. E-mail: conawayhowardh{at}uams.edu.

Dosage-dependent release of ⁴⁵Ca was observed from prelabeled mouse calvarial bones after treatment with two thiazolidinediones, troglitazone and ciglitazone. Release of ⁴⁵Ca by ciglitazone was decreased by the osteoclast inhibitors acetazolamide, calcitonin, 3-amino-1-hydroxypropylidene-1,1-bisphosphonate, and IL-4, but not affected by the peroxisome proliferator-activated receptor antagonist, GW 9662, the mitotic inhibitor, hydroxyurea, or indomethacin. Enhanced expression of receptor activator of nuclear factor-B ligand (RANKL) mRNA and protein and decreased osteoprotegerin (OPG) mRNA and protein were noted after ciglitazone treatment of calvariae. Ciglitazone and RANKL each caused increased mRNA expression of osteoclast markers: calcitonin receptor, tartrate-resistant acid phosphatase, cathepsin K, matrix metalloproteinase-9, integrin ß3, and nuclear factor of activated T cells 2. OPG inhibited mRNA expression of RANKL stimulated by ciglitazone, mRNA expression of osteoclast markers stimulated by ciglitazone and RANKL, and ⁴⁵Ca release stimulated by troglitazone and ciglitazone. Increased expression of IL-1 mRNA by ciglitazone was not linked to resorption stimulated by the thiazolidinedione. Ciglitazone did not increase adipogenic gene expression but enhanced osteocalcin mRNA in calvariae. In addition to exhibiting sensitivity to OPG, data indicate that stimulation of osteoclast differentiation and activity by thiazolidinediones may occur by a nonperoxisome proliferator-activated receptor -dependent pathway that does not require cell proliferation, prostaglandins, or IL-1 but is characterized by an increased RANKL to OPG ratio.

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