Bone Abstracts

Activation of p38 MAPK by RANKL is regulated by the scaffolding protein receptor for activated C-kinase 1 (RACK1) in osteoclast precursors, whereas it is unclear whether RACK1 can also affect in mature osteoclasts. In this study, to identify that the interaction of RACK1 with c-Src is essential for osteoclast function, we generated several mutants affecting the RACK1-c-Src association. A RACK1 mutant protein (mutations of tyrosine 228 and 246 residues to phenylalanine) disrupted interaction with c-Src and significantly decreased the phosphorylation level of c-Src. Furthermore, the mutant impaired the integrity of actin cytoskeleton and bone resorption activity of osteoclasts. Remarkably, Lysine 152 within the SH2 domain of c-Src is an important residue of interaction between RACK1 and c-Src. The bone-resorbing activity of osteoclasts is diminished by the c-Src K152R mutant (mutation of lysine 152 into arginine). These findings suggest that RACK1 plays a critical role in regulating osteoclast function through its ability to interact with c-Src and modulate its activity, which will help to develop new anti-resorptive therapies for preventing bone loss-related diseases.

Disclosure: The authors declared no competing interests.