Fluoride decreased osteoclastic bone resorption through the inhibition of NFATc1 gene expression

Area of Science:

• Bone Biology
• Cellular Physiology
• Fluoride Toxicology

Background:

• Osteoclasts are crucial for bone resorption, and their regulation is key to bone homeostasis.
• The molecular mechanisms underlying fluoride's impact on osteoclast function remain incompletely understood.
• Previous research has explored fluoride's effects on osteoclasts for two decades, highlighting a need for mechanistic clarity.

Purpose of the Study:

• To investigate the precise effects of fluoride on osteoclast formation, function, and regulatory pathways.
• To elucidate the molecular mechanisms by which fluoride influences osteoclast activity and bone resorption.

Main Methods:

• Osteoclasts were generated from mouse bone marrow macrophages.
• Cells were treated with receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF).
• The impact of varying fluoride concentrations (≤ 8 mg/L and 0.5 mg/L) on osteoclast formation, resorption, and gene expression was assessed.

Main Results:

• Fluoride concentrations up to 8 mg/L did not affect osteoclast formation.
• A fluoride concentration of 0.5 mg/L significantly reduced osteoclast bone resorption.
• Fluoride inhibited the expression of nuclear factor of active T cells (NFAT) c1 and its downstream genes involved in acidification and proteolysis, including dendritic cell-specific transmembrane protein, c-Src, vacuolar (H+) ATPase v0 domain (dV-ATPase), matrix metalloproteinase 9 (MMP-9), and cathepsin K.

Conclusions:

• Fluoride exhibits distinct effects on osteoclast formation versus function.
• Fluoride at 0.5 mg/L impairs osteoclast resorption activity by downregulating NFATc1 and its target genes.
• The findings suggest that fluoride's molecular mechanism involves the inhibition of NFATc1-mediated pathways, impacting osteoclast acidification and enzymatic secretion.