Rotenone impairs osteoclastogenesis by inhibiting cell migration: insights from machine learning

Area of Science:

• Cell Biology
• Metabolism
• Biochemistry

Background:

• Osteoclast precursors (OCPs) migration and fusion are vital for osteoclastogenesis, requiring significant energy.
• Oxidative phosphorylation (OXPHOS) is the primary energy pathway, but its specific role in OCP migration is not fully understood.

Purpose of the Study:

• To investigate the metabolic regulation of osteoclast migration.
• To determine the effects of OXPHOS inhibition on OCP migration.
• To identify genes linked to osteoclast dysfunction in osteoporosis.

Main Methods:

• Used rotenone, an OXPHOS inhibitor, to suppress energy production in OCPs.
• Employed bioinformatics and machine learning to identify genes associated with osteoclast dysfunction.
• Quantified OCP migratory capacity using optical tweezers.

Main Results:

• Rotenone inhibited osteoclastogenesis and significantly impaired OCP migration.
• Despite decreased OXPHOS, intracellular ATP levels paradoxically increased, indicating migration impairment is not due to energy shortage.
• Identified key genes regulating migration and adhesion, whose expression was suppressed by rotenone.

Conclusions:

• Rotenone inhibits osteoclastogenesis by impairing OCP migration through a mechanism independent of overall energy status.
• This study uncovers a novel pathway for rotenone's action on osteoclasts.
• Identified specific genes critical for osteoclast function and migration, potentially relevant for osteoporosis treatment.