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LY411575, a potent γ‐secretase inhibitor, suppresses osteoclastogenesis in vitro and LPS‐induced calvarial osteolysis in vivo
Author(s) -
Chen Xinwei,
Chen Xuzhuo,
Zhou Zhihang,
Qin An,
Wang Yexin,
Fan Baoting,
Xu Weifeng,
Zhang Shanyong
Publication year - 2019
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.28699
Subject(s) - osteoclast , bone resorption , osteolysis , in vivo , mapk/erk pathway , cancer research , chemistry , microbiology and biotechnology , in vitro , signal transduction , medicine , biology , biochemistry , surgery
Abstract A series of osteolytic bone diseases are usually related to excessive bone resorption and osteoclast formation. Thus, agents or drugs which can target osteoclast development and attenuate bone loss are potentially considerable in preventing and treating of bone lytic diseases. In recent years, many studies have reported that Notch signaling has substantial impacts on the process of osteoclast differentiation, maturation, and bone destruction. In the present study, we showed that LY411575, a γ‐secretase inhibitor, could potently suppress osteoclast differentiation, osteoclast‐specific gene expression, and bone resorption via suppressing Notch/HES1/MAPK (ERK and p38)/Akt‐mediated NFATc1 induction in vitro. Consistent with in vitro results, LY411575 exhibited protective effects in lipopolysaccharides‐induced calvarial bone destruction in vivo. Collectively, these results indicate that LY411575 may have therapeutic potential in the treatment of osteoclast‐mediated osteolytic bone diseases.