Molecular mechanism of thiazolidinedione-mediated inhibitory effects on osteoclastogenesis
Authors: Huixian Hong
Ping Qiao
Amy H Warriner
Yongjun Wang
Dongfeng Zhao
Zhenqi Shi
Xu Feng
Journal: PloS one (2014)
Discipline: Multidisciplinary
Keywords: Thiazolidinediones; osteoclastogenesis; molecular mechanism; RANKL; NFATc1
Affiliations: Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China; Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America., Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America., Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America., Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.

Abstract:  Thiazolidinediones are synthetic peroxisome proliferator-activated receptor γ agonists used to treat type 2 diabetes mellitus. Clinical evidence indicates that thiazolidinediones increase fracture risks in type 2 diabetes mellitus patients, but the mechanism by which thiazolidinediones augment fracture risks is not fully understood. Several groups recently demonstrated that thiazolidinediones stimulate osteoclast formation, thus proposing that thiazolidinediones induce bone loss in part by prompting osteoclastogenesis. However, numerous other studies showed that thiazolidinediones inhibit osteoclast formation. Moreover, the molecular mechanism by which thiazolidinediones modulate osteoclastogenesis is not fully understood. Here we independently address the role of thiazolidinediones in osteoclastogenesis in vitro and furthermore investigate the molecular mechanism underlying the in vitro effects of thiazolidinediones on osteoclastogenesis. Our in vitro data indicate that thiazolidinediones dose-dependently inhibit osteoclastogenesis from bone marrow macrophages, but the inhibitory effect is considerably reduced when bone marrow macrophages are pretreated with RANKL. In vitro mechanistic studies reveal that thiazolidinediones inhibit osteoclastogenesis not by impairing RANKL-induced activation of the NF-κB, JNK, p38 and ERK pathways in bone marrow macrophages. Nonetheless, thiazolidinediones inhibit osteoclastogenesis by suppressing RANKL-induced expression of NFATc1 and c-Fos, two key transcriptional regulators of osteoclastogenesis, in bone marrow macrophages. In addition, thiazolidinediones inhibit the RANKL-induced expression of osteoclast genes encoding matrix metalloproteinase 9, cathepsin K, tartrate-resistant acid phosphatase and carbonic anhydrase II in bone marrow macrophages. However, the ability of thiazolidinediones to inhibit the expression of NFATc1, c-Fos and the four osteoclast genes is notably weakened in RANKL-pretreated bone marrow macrophages. These in vitro studies have not only independently demonstrated that thiazolidinediones exert inhibitory effects on osteoclastogenesis but have also revealed crucial new insights into the molecular mechanism by which thiazolidinediones inhibit osteoclastogenesis. 

Retracted: Yes

PubPeer comments:
 Figure 3c. Much more similar than you would expect. ![file] , 
 Thank you for your comment. We are considering it seriously. The matter is now under investigation. Information on the outcome and appropriate responses will be posted in the close future. , 
 2021 correction. https: www.nature.com articles s41388-021-01648-1 Following publication of this article, the authors became aware of an error in Fig. 3c. In the published paper, the immunoblots for p21WAF1 were inadvertently duplicated during the construction of the figure. A corrected Fig. 3c is provided below. The results and conclusions of this article are not affected by this modification. The authors apologize to readers for any inconvenience caused. , 
 Figures 4c and 5c. Much more similar than expected. ![file] ,