SH3P2 suppresses osteoclast differentiation through restricting membrane localization of myosin 1E

Area of Science:

• Bone Biology and Osteoclast Function
• Cellular Regulation of Bone Remodeling

Background:

• Osteoclasts are critical for bone resorption, and their differentiation is tightly regulated.
• The precise role of Src homology 3 (SH3) domain-containing protein-2 (SH3P2) in osteoclast biology was previously unclear.

Purpose of the Study:

• To elucidate the function of SH3P2 in osteoclast differentiation and bone resorption.
• To investigate the molecular mechanisms by which SH3P2 influences osteoclast formation.

Main Methods:

• Utilized SH3P2 knockout (KO) mice to assess bone mass and osteoclast localization.
• Examined osteoclast differentiation in vitro using bone marrow-derived macrophages stimulated with macrophage colony-stimulating factor and receptor activator of nuclear factor-κB ligand (RANKL).
• Investigated the interaction between SH3P2 and myosin 1E (Myo1E) following RANKL stimulation.

Main Results:

• SH3P2 KO mice exhibited decreased femoral trabecular bone mass and increased osteoclast presence on tibial bone.
• Osteoclast differentiation was enhanced in macrophages lacking SH3P2.
• RANKL-induced SH3P2 dephosphorylation promoted Myo1E association with SH3P2, hindering Myo1E's plasma membrane localization.

Conclusions:

• SH3P2 acts as a suppressor of osteoclast differentiation and bone resorption.
• SH3P2 regulates osteoclast formation by modulating the localization of the actin-dependent motor protein Myo1E.
• These findings reveal a novel mechanism by which SH3P2 controls cell-to-cell fusion during osteoclastogenesis.