Thiazolidinediones inhibit TNF-alpha-mediated osteoclast differentiation of RAW264.7 macrophages and mouse bone marrow cells through downregulation of NFATc1.
TNF-alpha plays critical roles in bone-resorbing diseases, such as rheumatoid arthritis. Recent evidence suggests that thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor gamma agonists, have anti-inflammatory effects. The aim of this study was to evaluate the effect of TZDs on the TNF-alpha-mediated osteoclastogenesis of osteoclast precursor cells. TNF-alpha treatment of RAW264.7 murine macrophages or mouse bone marrow cells induced significant multinuclear osteoclast formation, and these differentiated osteoclast cells possessed bone-resorbing activity. The TZD drugs, rosiglitazone and pioglitazone, significantly inhibited TNF-alpha-induced osteoclast differentiation from both cell types and subsequent bone resorption. Reverse transcriptase-polymerase chain reaction, reporter gene assays, and Western blot results revealed that TZD treatment significantly suppressed NFATc1 expression. Moreover, GW9662 (a peroxisome proliferator-activated receptor gamma antagonist) prevented the inhibitory effect of TZDs on NFATc1 expression and osteoclast differentiation. In summary, our results demonstrate that TZDs inhibit TNF-alpha-mediated osteoclast differentiation by downregulation of NFATc1 expression. This observation increases the therapeutic applications of TZDs in inflammatory bone-resorbing diseases.
Yang
Chia-Ron
CR
School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan. cryang@ntu.edu.tw
Lai
Chang-Chi
CC
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D015536:Down-Regulation; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics*; D010010:Osteoclasts / Q000187:drug effects; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D000077205:Pioglitazone; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D000077205:Pioglitazone