Open Access
l ‐tetrahydropalmatine suppresses osteoclastogenesis in vivo and in vitro via blocking RANK‐TRAF6 interactions and inhibiting NF‐κB and MAPK pathways
Author(s) -
Zhi Xin,
Wang Lipeng,
Chen Huiwen,
Fang Chao,
Cui Jin,
Hu Yan,
Cao Liehu,
Weng Weizong,
Zhou Qirong,
Qin Longjuan,
Song Hongyuan,
Wang Yajun,
Wang Yao,
Jiang Hao,
Li Xiaoqun,
Wang Sicheng,
Chen Xiao,
Su Jiacan
Publication year - 2020
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.14790
Subject(s) - rankl , mapk/erk pathway , nf κb , chemistry , osteoclast , electrophoretic mobility shift assay , p38 mitogen activated protein kinases , in vivo , microbiology and biotechnology , transcription factor , rank ligand , osteoprotegerin , western blot , activator (genetics) , iκbα , receptor , signal transduction , biology , biochemistry , gene
Abstract Bone homeostasis is delicately orchestrated by osteoblasts and osteoclasts. Various pathological bone loss situations result from the overactivated osteoclastogenesis. Receptor activator of nuclear factor κB ligand (RANKL)‐activated NF‐κB and MAPK pathways is vital for osteoclastogenesis. Here, we for the first time explored the effects of l ‐tetrahydropalmatine ( l ‐THP), an active alkaloid derived from corydalis, on the formation and function of osteoclasts in vitro and in vivo. In RAW264.7 cells and bone marrow monocytes cells (BMMCs), l ‐THP inhibited osteoclastic differentiation at the early stage, down‐regulated transcription level of osteoclastogenesis‐related genes and impaired osteoclasts functions. Mechanically, Western blot showed that l ‐THP inhibited the phosphorylation of P50, P65, IκB, ERK, JNK and P38, and the electrophoretic mobility shift assay (EMSA) revealed that DNA binding activity of NF‐κB was suppressed, ultimately inhibiting the expression of nuclear factor of activated T cells (NFATc1). Besides, Co‐immunoprecipitation indicated that l ‐THP blocked the interactions of RANK and TNF receptor associated factor 6 (TRAF6) at an upstream site. In vivo, l ‐THP significantly inhibited ovariectomy‐induced bone loss and osteoclastogenesis in mice. Collectively, our study demonstrated that l ‐THP suppressed osteoclastogenesis by blocking RANK‐TRAF6 interactions and inhibiting NF‐κB and MAPK pathways. l ‐THP is a promising agent for treating osteoclastogenesis‐related diseases such as post‐menopausal osteoporosis.