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Paclitaxel inhibits osteoclast formation and bone resorption via influencing mitotic cell cycle arrest and RANKL‐induced activation of NF‐κB and ERK
Author(s) -
Ang Estabelle S. M.,
Pavlos Nathan J.,
Chim Shek Man,
Feng Hao Tian,
Scaife Robin M.,
Steer James H.,
Zheng Ming H.,
Xu Jiake
Publication year - 2012
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.23423
Subject(s) - osteolysis , rankl , osteoclast , bone resorption , paclitaxel , cancer research , chemistry , mapk/erk pathway , bone metastasis , nf κb , microbiology and biotechnology , medicine , activator (genetics) , apoptosis , metastasis , biology , receptor , signal transduction , cancer , biochemistry , surgery
Pathological bone destruction (osteolysis) is a hallmark of many bone diseases including tumor metastasis to bone, locally osteolytic giant cell tumor (GCT) of bone, and Paget's disease. Paclitaxel is frequently prescribed in the treatment of several malignant tumors where it has been shown to exert beneficial effects on bone lesions. However, the mechanism(s) through which paclitaxel regulates osteoclast formation and function remain ill defined. In the present study, we demonstrate that paclitaxel dose‐dependently inhibits receptor activator of nuclear factor‐kappa B ligand (RANKL)‐induced osteoclastogenesis in both RAW264.7 cells and mouse bone marrow macrophage (BMM) systems. In addition, paclitaxel treatment reduces the bone resorptive activity of human osteoclasts derived from GCT of bone, and attenuates lipopolysaccharide (LPS)‐induced osteolysis in a mouse calvarial model. Complementary cellular and biochemical analyses revealed that paclitaxel induces mitotic arrest of osteoclastic precursor cells. Furthermore, luciferase reporter gene assays and western blot analysis indicate that paclitaxel modulates key RANKL‐induced activation pathways that are essential to osteoclast formation including NF‐κB and ERK. Collectively, our findings demonstrate a role for paclitaxel in the regulation of osteoclast formation and function and uncover potential mechanism(s) through which paclitaxel alleviates pathological osteolysis. J. Cell. Biochem. 113: 946–955, 2012. © 2011 Wiley Periodicals, Inc.