Centrala begrepp
Transient reactive oxygen species (ROS) signaling during osteoclast differentiation triggers a shift from reduced to oxidized species of La protein, promoting its trafficking from the nucleus to the cell surface where it regulates osteoclast fusion and bone resorptive function.
Sammanfattning
The content discusses the role of redox signaling in regulating the localization and function of La protein during osteoclast formation and bone resorption. Key points:
- Osteoclast fusion and bone resorption are promoted by an oxidized species of cell surface-associated La protein, which is distinct from the reduced, nuclear form of La.
- Transient ROS signaling during osteoclast differentiation triggers the shift from reduced to oxidized La species, leading to La's dephosphorylation and delivery to the osteoclast surface.
- The oxidation of critical cysteine residues (Cys232 and Cys245) in the C-terminal half of La is required for its ability to promote osteoclast fusion and resorption.
- Suppressing ROS signaling with NAC inhibits the transition from reduced to oxidized La species, prevents La's surface delivery, and impairs osteoclast multinucleation.
- Exogenous addition of the C-terminal La fragment can rescue the fusion-inhibiting effects of NAT, but this rescue is dependent on the presence of the critical cysteine residues.
- The findings suggest that redox-dependent changes in La trafficking and function play a critical role in regulating osteoclast fusion and bone resorption, and represent a potential therapeutic target for skeletal disorders.
Statistik
Transient ROS signaling is induced during RANKL-initiated osteoclast differentiation.
Inhibition of ROS signaling with NAC suppresses the shift from reduced to oxidized La species in differentiating osteoclasts.
Mutation of Cys232 and Cys245 in the C-terminal half of La abrogates its ability to promote osteoclast fusion.
Exogenous addition of the wild-type C-terminal La fragment can rescue the fusion-inhibiting effects of NAC, but the cysteine mutant fragment cannot.
Citat
"Transient, moderate increases in ROS levels, referred to as redox signaling 12,13 or a mild oxidative stress 14, play important roles in diverse cellular differentiation processes15-17."
"Finding that the surface pool of La that manages osteoclast size and resorptive function is primarily composed of an oxidized La molecular species."
"Our data, which indicate that fusion competence in osteoclast precursors depends on ROS signaling, can be, at least partially, explained by the oxidation-dependent changes in the structure of La protein and its nucleo-cytoplasmic-cell surface shuttling."