PPARγ inhibits osteogenesis via the down-regulation of the expression of COX-2 and NOS in rats

Peroxisome proliferator-activated receptor gamma (PPAR gamma), a ligand-activated transcription factor, is considered as an anti-osteoblastic factor associated with adiposity and the elderly osteoporosis due to a defect in osteoblastogenesis. We have found that oral administration of PPAR gamma activator rosiglitazone decreased tibia BNID and serum ALP but left serum calcium and osteoclast marker C-terminal telopeptide unaffected. In addition, we examined the inhibitory mechanisms of PPAR gamma on the bone fort-nation by using PPAR gamma activators ciglitazone and 15-deoxy-Delta(12,14)- prostaglandin-J2 (15d-PGJ2). Our data indicated that PPAR gamma ligands decreased both mineralized bone nodules and alkaline phosphatase (ALP) activities in cultured primary osteoblasts. Reverse transcription polymerase chain reaction (RT-PCR) showed that the expression of bone morphogenetic protem-2 (BMP-2) and osteocalcin (OCN) was inhibited by ciglitizone and 15d-PGJ2. Furthermore, PPAR gamma ligands inhibited NF-kappa B associated downstream COX-2 and NOS osteogenic signaling. The ultrasound (US)-induced elevation of COX-2 and NOS expression and nitric oxide (NO) production were attenuated in the presence of PPAR gamma ligands. Furthermore, local administration of PPAR gamma ligands into the metaphysis of rat tibia decreased the bone volume in secondary spongiosa. These results suggest that the activation of PPAR gamma inhibits osteoblastic differentiation and the expression of several anabolic mediators involved in bone formation. These data may reflect osteoporosis and less bone formation in the aging people and patients treated with thiazolidinediones. (C) 2007 Elsevier Inc. All rights reserved.