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.