Small molecule inhibitor RepSox prevented ovariectomy‐induced osteoporosis by suppressing osteoclast differentiation and bone resorption. Issue 12 (30th July 2018)

• Record Type: Journal Article
• Authors: Mei, Liangwei; Sang, Wenhua; Chen, Zhenzhong; Zheng, Lin; Jin, Kangtao; Lou, Chao; Huang, Wenjun; He, Dengwei
• Is Part Of: Journal of cellular physiology. Volume 233:Issue 12(2018:Dec.)
• Page Start: 9724
• Page End: 9738
• Publication Date: 2018-07-30
• Subjects: osteoclast -- ovariectomy (OVX) -- RepSox -- Smad3 -- TGFβRI; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.26914
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract : Osteoporosis (OP) is a serious metabolic disease that, due to the increased number or function of osteoclasts, results in increased bone brittleness and, therefore, fragile fracture. Some recent studies report the importance of the transforming growth factor β (TGFβ) pathway in bone homeostasis. RepSox is a small molecule inhibitor of TGFβRI that has a wide range of potential application in clinical medicine, except OP. The aim of our study is to evaluate the effects of RepSox on the differentiation and bone resorption of osteoclasts in vitro and in vivo in an ovariectomy (OVX)‐induced OP model. An initial analysis showed TGFβRI messenger RNA expression in both bone samples and bone cells. In the in vitro study, RepSox inhibited the receptor activator of nuclear factor κB ligand (RANKL)‐induced osteoclast differentiation and bone resorption activity. Real‐time polymerase chain reaction (PCR) analysis showed that RepSox suppressed osteoclastic marker gene expression in both dose‐dependent and time‐dependent manners. In addition, RepSox did not affect osteoblast differentiation, migration or osteoblastic‐specific gene expression in vitro. Furthermore, western blot analysis indicated the underlying mechanisms of the RepSox suppression of osteoclastogenesis via the Smad3 and c‐Jun N‐terminal kinase/activator protein‐1 (JNK/AP‐1) signaling pathways. Finally, our animal experiments revealed that RepSox prevented OVX‐induced bone loss in vivo. Together, our data suggest that RepSox regulates osteoclast differentiation, bone resorption, and OVX‐induced OP via the suppression of the Smad3 and JNK/AP‐1 pathways. Abstract : Bone destruction or osteolysis, marked by excessive osteoclastic bone resorption, is a very common medical condition. Identification of agents that can effectively suppress excessive osteoclast formation and function is crucial for prevention and treatment of osteolytic conditions, such as osteoporosis. In the present paper, we report that RepSox inhibits osteoclast formation in vitro and in vivo, suggesting that it is potentially valuable in the treatment of osteoclast‐related diseases.