FTY720 Attenuates LPS-Induced Inflammatory Bone Loss by Inhibiting Osteoclastogenesis via the NF-κB and HDAC4/ATF...

Area of Science:

• Biomedical Science
• Cell Biology
• Pharmacology

Background:

• Osteoclast (OC) dysfunction drives various osteolytic diseases, including osteoporosis and tumor-induced bone loss.
• Developing therapeutic strategies to correct OC dysregulation is crucial for treating skeletal diseases.
• FTY720 (fingolimod) is an established drug for multiple sclerosis with known anti-inflammatory properties.

Purpose of the Study:

• To investigate the effects of FTY720 on osteoclastogenesis and OC function.
• To elucidate the molecular mechanisms underlying FTY720's action on osteoclasts.
• To evaluate FTY720's therapeutic potential in preclinical models of osteolysis.

Main Methods:

• In vitro studies assessed FTY720's impact on osteoclast differentiation and function.
• Molecular analyses examined the effects of FTY720 on NF-κB, HDAC4, and ATF4 signaling pathways.
• In vivo experiments utilized a lipopolysaccharide (LPS)-induced calvarial osteolysis model in mice.

Main Results:

• FTY720 significantly inhibited osteoclastogenesis and OC function.
• FTY720 suppressed osteoclast formation by inhibiting nuclear factor kappa-B (NF-κB) signaling.
• FTY720 upregulated histone deacetylase 4 (HDAC4) and downregulated activating transcription factor 4 (ATF4) expression.
• In vivo, FTY720 treatment prevented LPS-induced calvarial osteolysis and reduced TRAP-positive OCs.

Conclusions:

• FTY720 demonstrates potent inhibition of osteoclastogenesis and OC-mediated bone resorption.
• The drug's mechanism involves modulation of NF-κB, HDAC4, and ATF4 signaling pathways.
• FTY720 shows promise as a therapeutic agent for skeletal diseases linked to osteoclast abnormalities.