Sestrin2 Regulates Osteoclastogenesis via the p62-TRAF6 Interaction

Area of Science:

• Bone Biology and Metabolism
• Cell Signaling Pathways
• Osteoclast Differentiation

Background:

• Receptor activator of nuclear factor-kappa B ligand (RANKL) signaling is crucial for osteoclast differentiation.
• Reactive oxygen species (ROS) and Sestrin2 play roles in cellular homeostasis, but Sestrin2's role in osteoclastogenesis is unknown.

Purpose of the Study:

• To investigate the role of Sestrin2 in the RANKL-RANK-TRAF6 signaling pathway during osteoclast differentiation.
• To determine if Sestrin2 influences bone mass and osteoclast formation.

Main Methods:

• Utilized Sestrin2 knockout (KO) mice and bone marrow-derived monocytes/macrophages (BMMs).
• Analyzed RANKL-induced osteoclast differentiation, NFATc1 expression, MAPK signaling, ROS generation, and Ca2+ oscillations.
• Investigated the interaction between TRAF6 and p62.

Main Results:

• Sestrin2 deletion increased bone mass and reduced osteoclast numbers.
• Osteoclast differentiation and function were decreased in Sesn2 KO BMMs due to inhibited NFATc1 expression.
• MAPK protein expression and RANKL-induced gene expression were lower in Sesn2 KO BMMs.
• ROS generation and Ca2+ oscillations were unaffected, but TRAF6/p62 interaction was reduced in Sesn2 KO BMMs.
• Re-expression of Sestrin2 restored TRAF6/p62 interaction and TRAP activity.

Conclusions:

• Sestrin2 plays a novel role in regulating bone homeostasis and osteoclast differentiation.
• Sestrin2 influences osteoclastogenesis by modulating NFATc1 expression and the TRAF6/p62 interaction.
• Targeting Sestrin2 may offer therapeutic strategies for bone-related disorders.