Proteasome inhibition suppress microgravity elevated RANK signaling during osteoclast differentiation

Area of Science:

• Space biology
• Cell biology
• Biochemistry

Background:

• Microgravity (µXg) causes bone loss in astronauts, necessitating countermeasures.
• Osteoclasts (OCLs) resorb bone, and their formation is enhanced under simulated µXg.
• The ubiquitin-proteasome pathway regulates OCL formation, but its role in µXg-induced bone resorption is unclear.

Purpose of the Study:

• To investigate the effect of proteasome inhibition on osteoclast differentiation and function under microgravity conditions.
• To elucidate the molecular mechanisms by which proteasome inhibition impacts osteoclastogenesis in µXg.

Main Methods:

• RAW264.7 preosteoclast cells and mouse bone marrow cultures were used.
• Cells were treated with proteasome inhibitor MG-132 under normal gravity and simulated µXg.
• RANK receptor expression, K48-linked poly-ubiquitination, SQSTM1/p62, c-Fos, c-Jun, and NFATc1 levels were analyzed.
• Osteoclast formation and bone resorption activity were assessed.

Main Results:

• MG-132 suppressed RANK expression and K48-linked poly-ubiquitination in preosteoclasts under µXg.
• Proteasome inhibition reduced SQSTM1/p62 expression and its co-localization with lysosomes.
• MG-132 decreased c-Fos and NFATc1 expression while altering p-c-Jun activity under µXg.
• Inhibition of osteoclast formation and bone resorption was observed in mouse bone marrow cultures.

Conclusions:

• Proteasome inhibition effectively suppresses osteoclast differentiation and bone resorption under microgravity.
• Targeting the ubiquitin-proteasome pathway, specifically K48-linked ubiquitination and p62 degradation, is a viable strategy.
• Proteasome inhibition offers a novel therapeutic approach to mitigate bone loss during space missions.