Disruption of the dynein-dynactin complex unveils motor-specific functions in osteoclast formation and bone resorption

• DOI: 10.1002/jbmr.1725
• Publication Date: 2012-08-08T16:12:48Z
• Authors: Pei Ying Ng; Tak Sum Cheng; Haibo Zhao; Shiqiao Ye; Estabelle SM Ang; Ee Cheng Khor; Hao-Tian Feng; Jiake Xu; Ming H Zheng; Nathan J Pavlos
• Keywords: Dynactin; Dynein ATPase

Abstract Osteoclastic bone resorption requires strict interplay between acidified carrier vesicles, motor proteins, and the underlying cytoskeleton in order to sustain specialized structural functional polarization of ruffled border. Cytoplasmic dynein, a large processive mechanochemical comprising heavy, intermediate, light chains coupled dynactin cofactor complex, powers unilateral motility diverse cargos microtubule minus-ends. We have recently shown that regulators dynein complex constitute critical components osteoclastic resorptive machinery. Here, by selectively modulating endogenous activity, we show integrity dynein-dynactin is an essential requirement for both osteoclast formation function. Systematic dissection revealed it differentially localized throughout RANKL-induced activation, undergoing microtubule-coupled reorganization upon establishment cellular polarization. In osteoclasts actively resorbing bone, intimately co-localizes with CAP-Gly domain-containing plus-end protein CLIP-170 at front, thus orientating border as domain. Unexpectedly, disruption exogenous p50/dynamitin expression retards vitro, owing largely prolonged mitotic stasis progenitor cells. More importantly, loss activity results drastic redistribution key intracellular organelles, including Golgi lysosomes, effect coincides impaired cathepsin K secretion diminished Collectively, these data unveil previously unrecognized role function, serving not only regulate their timely maturation but also delivery osteolytic cargo process. © 2013 American Society Bone Mineral Research