Paclitaxel inhibits osteoclast formation and bone resorption via influencing mitotic cell cycle arrest and RANKL-induced activation of NF-κB and ERK.
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.
School of Dentistry, University of Western Australia, Nedlands, WA 6009, Australia.
Estabelle S M
ES
Ang
Nathan J
NJ
Pavlos
Shek Man
SM
Chim
Hao Tian
HT
Feng
Robin M
RM
Scaife
James H
JH
Steer
Ming H
MH
Zheng
Jiake
J
Xu
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000473:pathology; D001862:Bone Resorption; D002460:Cell Line; D003599:Cytoskeleton / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018212:Giant Cell Tumor of Bone / Q000473:pathology; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010014:Osteolysis; D017239:Paclitaxel / Q000494:pharmacology*; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D016328:NF-kappa B; D053245:RANK Ligand; D048049:Extracellular Signal-Regulated MAP Kinases; D017239:Paclitaxel