PMID- 21225243
OWN - NLM
STAT- MEDLINE
DCOM- 20110729
LR  - 20211020
IS  - 1432-1912 (Electronic)
IS  - 0028-1298 (Linking)
VI  - 383
IP  - 3
DP  - 2011 Mar
TI  - Zoledronic acid inhibits RANK expression and migration of osteoclast precursors 
      during osteoclastogenesis.
PG  - 297-308
LID - 10.1007/s00210-010-0596-4 [doi]
AB  - Bisphosphonates have been known to directly inhibit bone resorption and promote 
      apoptosis in mature osteoclasts. Although bisphosphonates have been recognized as 
      the most effective drugs to treat osteoporosis and bone cancer metastasis, the 
      exact effects and mechanism(s) of bisphosphonates on osteoclastogenesis are 
      unclear. The aim of this study was to clarify whether nitrogen-containing 
      bisphosphonates affect recruitment and differentiation in osteoclasts. We 
      examined the effects of zoledronic acid on receptor activator of NF-kappaB (RANK) 
      expression and cell migration during osteoclastogenesis in two types of 
      osteoclast precursors, RAW264.7 cells and Bone marrow cells (BMCs). Tumor 
      necrosis factor-alpha (TNF-alpha) and RANK ligand (RANKL) upregulated RANK expression in 
      RAW264.7 and BMCs in the presence of macrophage colony stimulating factor in a 
      time-dependent manner. Zoledronic acid (30 and 50 muM) had no effect on cell 
      viability in osteoclast precursors after 36 h of cultivation. Zoledronic acid (10 
      and 30 muM) strongly inhibited TNF-alpha- and RANKL-induced upregulation of RANK in a 
      dose-dependent manner. The inhibitory effects on RANK expression were likely to 
      be associated with the suppression of the NF-kappaB pathway, but not other downstream 
      signaling pathways. Zoledronic acid (30 muM) also suppressed the TNF-alpha- and 
      RANKL-induced migration of precursors by inhibiting the mevalonic acid pathway. 
      Our results suggest that nitrogen-containing bisphosphonates not only inhibit 
      mature osteoclasts but also prevent osteoclast precursors from differentiating 
      and migrating towards inflammatory osteolysis lesions.
FAU - Kimachi, Keiichiro
AU  - Kimachi K
AD  - Department of Physiological Science and Molecular Biology, Fukuoka Dental 
      College, Tamura 2-15-1 Sawara-ku, Fukuoka 8140193, Japan.
FAU - Kajiya, Hiroshi
AU  - Kajiya H
FAU - Nakayama, Shuji
AU  - Nakayama S
FAU - Ikebe, Tetsuro
AU  - Ikebe T
FAU - Okabe, Koji
AU  - Okabe K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110112
PL  - Germany
TA  - Naunyn Schmiedebergs Arch Pharmacol
JT  - Naunyn-Schmiedeberg's archives of pharmacology
JID - 0326264
RN  - 0 (Diphosphonates)
RN  - 0 (Diterpenes)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (Imidazoles)
RN  - 0 (Isoenzymes)
RN  - 0 (NF-kappa B)
RN  - 0 (Nfkbia protein, mouse)
RN  - 0 (RANK Ligand)
RN  - 0 (Receptor Activator of Nuclear Factor-kappa B)
RN  - 0 (Tnfrsf11a protein, mouse)
RN  - 0 (Tnfsf11 protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
RN  - 6XC1PAD3KF (Zoledronic Acid)
RN  - AIA02AJA3A (geranylgeraniol)
RN  - EC 3.1.3.2 (Acid Phosphatase)
RN  - EC 3.1.3.2 (Tartrate-Resistant Acid Phosphatase)
SB  - IM
MH  - Acid Phosphatase/metabolism
MH  - Animals
MH  - Bone Marrow Cells/cytology/drug effects/metabolism
MH  - Bone Resorption/metabolism
MH  - Cell Differentiation/*drug effects
MH  - Cell Line, Tumor
MH  - Cell Movement/*drug effects
MH  - Diphosphonates/*pharmacology
MH  - Diterpenes/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Gene Expression/drug effects/genetics
MH  - I-kappa B Proteins/metabolism
MH  - Imidazoles/*pharmacology
MH  - Isoenzymes/metabolism
MH  - Macrophages/cytology/drug effects/metabolism
MH  - Mice
MH  - Mice, Inbred Strains
MH  - NF-KappaB Inhibitor alpha
MH  - NF-kappa B/metabolism
MH  - Osteoclasts/*cytology/metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Prenylation/drug effects
MH  - RANK Ligand/pharmacology
MH  - Receptor Activator of Nuclear Factor-kappa B/genetics/*metabolism
MH  - Signal Transduction/drug effects/physiology
MH  - Stem Cells/*cytology/drug effects/*metabolism
MH  - Tartrate-Resistant Acid Phosphatase
MH  - Transcription, Genetic/drug effects
MH  - Tumor Necrosis Factor-alpha/pharmacology
MH  - Up-Regulation/drug effects/genetics
MH  - Zoledronic Acid
EDAT- 2011/01/13 06:00
MHDA- 2011/07/30 06:00
CRDT- 2011/01/13 06:00
PHST- 2010/09/06 00:00 [received]
PHST- 2010/12/21 00:00 [accepted]
PHST- 2011/01/13 06:00 [entrez]
PHST- 2011/01/13 06:00 [pubmed]
PHST- 2011/07/30 06:00 [medline]
AID - 10.1007/s00210-010-0596-4 [doi]
PST - ppublish
SO  - Naunyn Schmiedebergs Arch Pharmacol. 2011 Mar;383(3):297-308. doi: 
      10.1007/s00210-010-0596-4. Epub 2011 Jan 12.