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1.
Endocrinology ; 148(6): 2669-80, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17332064

ABSTRACT

Peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates both glucose metabolism and bone mass. Recent evidence suggests that the therapeutic modulation of PPARgamma activity with antidiabetic thiazolidinediones elicits unwanted effects on bone. In this study, the effects of rosiglitazone on the skeleton of growing (1 month), adult (6 month), and aged (24 month) C57BL/6 mice were determined. Aging was identified as a confounding factor for rosiglitazone-induced bone loss that correlated with the increased expression of PPARgamma in bone marrow mesenchymal stem cells. The bone of young growing mice was least affected, although a significant decrease in bone formation rate was noted. In both adult and aged animals, bone volume was significantly decreased by rosiglitazone. In adult animals, bone loss correlated with attenuated bone formation, whereas in aged animals, bone loss was associated with increased osteoclastogenesis, mediated by increased receptor activator of nuclear factor-kappaB ligand (RANKL) expression. PPARgamma activation led to changes in marrow structure and function such as a decrease in osteoblast number, an increase in marrow fat cells, an increase in osteoclast number, and a loss of the multipotential character of marrow mesenchymal stem cells. In conclusion, rosiglitazone induces changes in bone reminiscent of aged bone and appears to induce bone loss by altering the phenotype of marrow mesenchymal stem cells.


Subject(s)
Aging , Bone Density/drug effects , Bone and Bones/physiology , Osteoporosis/pathology , Thiazolidinediones/pharmacology , Animals , Bone Resorption/pathology , Bone and Bones/anatomy & histology , Bone and Bones/drug effects , Cell Differentiation/drug effects , Compressive Strength/drug effects , Male , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/drug effects , Mice , Mice, Inbred C57BL , Osteoblasts/cytology , Osteoblasts/drug effects , Osteoclasts/cytology , Osteoclasts/drug effects , Osteogenesis/drug effects , Rosiglitazone , Tomography, X-Ray Computed
2.
Bone ; 38(1): 74-84, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16137931

ABSTRACT

Thiazolidinediones are effective anti-diabetic drugs that improve insulin sensitivity through the activation of the nuclear receptor and adipocyte-specific transcription factor, peroxisome proliferator-activated receptor gamma (PPAR-gamma). Recent evidence suggests that PPAR-gamma also controls bone cell development and bone homeostasis. In mice, PPAR-gamma insufficiency results in increased bone mass, whereas administration of the specific PPAR-gamma agonist rosiglitazone leads to bone loss and increased bone marrow adiposity. Although the pro-adipocytic and anti-osteoblastic activities of PPAR-gamma can be separated in vitro using ligands with distinct chemical structures, little evidence exists supporting this functional separation in vivo. Netoglitazone (MCC-555, RWJ-241947) is a thiazolidinedione, which acts as either a full or partial PPAR-gamma agonist, or antagonist, in a cell type specific manner. In this study, the pro-adipocytic and anti-osteoblastic activities of netoglitazone were evaluated in vitro, using both U-33/gamma2 cells as a model of marrow mesenchymal cell differentiation under the control of PPAR-gamma2 and primary bone marrow cultures, and in vivo in C57BL/6 mice. In vitro, netoglitazone induced adipocyte and inhibited osteoblast formation in a PPAR-gamma2-dependent manner; however, it was 100-fold less effective than rosiglitazone. In vivo, the administration of netoglitazone at an effective hyperglycemic dose (10 microg/g body weight/day) did not result in trabecular bone loss. Bone quality parameters such as bone mineral density and bone microarchitecture were not affected in netoglitazone-treated animals. The observed lack of an in vivo effect of netoglitazone on bone was entirely consistent with its low anti-osteoblastic activity in vitro. In contrast to the observed in vitro effects, netoglitazone in vivo effectively induced marrow adipocyte formation and induced changes in the weights of extramedullary fat depots. Consistent with these cell type-specific effects, expression of the adipocyte-specific gene marker FABP4/aP2 was increased, whereas the expression of osteoblast-specific gene markers, Runx2, Dlx5, osteocalcin, and collagen were not affected by netoglitazone. In conclusion, netoglitazone is a member of a new class of PPAR-gamma ligands with distinct anti-diabetic, anti-osteoblastic, and pro-adipocytic activities in vivo.


Subject(s)
Adipocytes/physiology , Cell Differentiation/physiology , Osteoblasts/physiology , Thiazoles/pharmacology , Adipocytes/drug effects , Animals , Bone Density/drug effects , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , Cell Culture Techniques , Cell Differentiation/drug effects , Cell Line , Culture Media , Dose-Response Relationship, Drug , Gene Expression Regulation/drug effects , Genetic Markers/drug effects , Ligands , Male , Mice , Mice, Inbred C57BL , Osteoblasts/drug effects , PPAR gamma , Reverse Transcriptase Polymerase Chain Reaction , Rosiglitazone , Thiazoles/agonists , Thiazolidinediones/agonists , Thiazolidinediones/pharmacology , Tomography, X-Ray Computed
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