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L-type Ca2+ channel agonist inhibits RANKL-induced osteoclast formation via NFATc1 down-regulation
- Source :
- Life Sciences. 89:159-164
- Publication Year :
- 2011
- Publisher :
- Elsevier BV, 2011.
-
Abstract
- Aims BayK 8644 is an L-type Ca 2+ channel agonist that enhances Ca 2+ influx and elevates cytosolic Ca 2+ . As intracellular calcium plays a key role in osteoclast formation, we investigated the effects of BayK 8644 in cultures of bone marrow-derived precursor cells with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappaB ligand (RANKL). Main methods We performed an osteoclast formation assay, a pit formation assay, real-time PCR, and Western blot analysis. Key findings BayK 8644 concentration-dependently suppressed osteoclastogenesis, as well as the expression of osteoclastic marker genes. It also decreased osteoclastic bone resorption on a dentine slice. While the RANKL-stimulated induction of IL-1β and IL-6 was not affected, TNF-α induction was reduced by BayK 8644 treatment. In addition, BayK 8644 blocked IκB degradation and the induction of nuclear factor of activated T cells c1 (NFATc1), the master regulator of osteoclast differentiation, following RANKL stimulation. Finally, forced expression of NFATc1 reversed the inhibitory effect of BayK 8644 on osteoclastogenesis, suggesting that NFATc1 is a downstream target for the anti-osteoclastogenic action of BayK 8644. Taken together, our data suggest that BayK 8644 has an anti-osteoclastogenic effect by inhibiting RANKL-induced activation of NF-κB pathways, thereby suppressing the gene expression of NFATc1 in osteoclast precursors. Significance Our results provide a molecular understanding of the inhibitory effect of the L-type Ca 2+ channel agonist, BayK 8644, on osteoclastogenesis.
- Subjects :
- musculoskeletal diseases
Agonist
medicine.medical_specialty
Calcium Channels, L-Type
medicine.drug_class
Genetic Vectors
Down-Regulation
Gene Expression
Osteoclasts
Bone Marrow Cells
Monocytes
General Biochemistry, Genetics and Molecular Biology
Calcium in biology
Bone resorption
Mice
Osteoclast
Internal medicine
medicine
Animals
Humans
Bone Resorption
General Pharmacology, Toxicology and Pharmaceutics
Receptor
Cells, Cultured
NFATC Transcription Factors
biology
Voltage-dependent calcium channel
Reverse Transcriptase Polymerase Chain Reaction
Tumor Necrosis Factor-alpha
Activator (genetics)
Chemistry
RANK Ligand
NF-kappa B
General Medicine
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
Cell biology
Mice, Inbred C57BL
Calcium Channel Agonists
Retroviridae
medicine.anatomical_structure
Endocrinology
RANKL
biology.protein
RNA
Indicators and Reagents
Signal Transduction
Subjects
Details
- ISSN :
- 00243205
- Volume :
- 89
- Database :
- OpenAIRE
- Journal :
- Life Sciences
- Accession number :
- edsair.doi.dedup.....919d3d45a1d1a3ccc5c3ba3be5fe9439