title: Disruption of the dynein-dynactin complex unveils motor-specific functions in osteoclast formation and bone resorption.
abstract: Osteoclastic bone resorption requires strict interplay between acidified carrier vesicles, motor proteins, and the underlying cytoskeleton in order to sustain the specialized structural and functional polarization of the ruffled border. Cytoplasmic dynein, a large processive mechanochemical motor comprising heavy, intermediate, and light chains coupled to the dynactin cofactor complex, powers unilateral motility of diverse cargos to microtubule minus-ends. We have recently shown that regulators of the dynein motor complex constitute critical components of the osteoclastic bone resorptive machinery. Here, by selectively modulating endogenous dynein activity, we show that the integrity of the dynein-dynactin motor complex is an essential requirement for both osteoclast formation and function. Systematic dissection of the osteoclast dynein-dynactin complex revealed that it is differentially localized throughout RANKL-induced osteoclast formation and activation, undergoing microtubule-coupled reorganization upon the establishment of cellular polarization. In osteoclasts actively resorbing bone, dynein-dynactin intimately co-localizes with the CAP-Gly domain-containing microtubule plus-end protein CLIP-170 at the resorptive front, thus orientating the ruffled border as a microtubule plus-end domain. Unexpectedly, disruption of the dynein-dynactin complex by exogenous p50/dynamitin expression retards osteoclast formation in vitro, owing largely to prolonged mitotic stasis of osteoclast progenitor cells. More importantly, loss of osteoclastic dynein activity results in a drastic redistribution of key intracellular organelles, including the Golgi and lysosomes, an effect that coincides with impaired cathepsin K secretion and diminished bone resorptive function. Collectively, these data unveil a previously unrecognized role for the dynein-dynactin motor complex in osteoclast formation and function, serving not only to regulate their timely maturation but also the delivery of osteolytic cargo that is essential to the bone resorptive process.
authors.affiliation: Centre for Orthopaedic Research, School of Surgery, The University of Western Australia, Nedlands, WA, Australia.
authors.forename: Pei Ying
authors.initials: PY
authors.lastname: Ng
authors.forename: Tak Sum
authors.initials: TS
authors.lastname: Cheng
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhao
authors.forename: Shiqiao
authors.initials: S
authors.lastname: Ye
authors.forename: Estabelle
authors.initials: E
authors.lastname: Sm Ang
authors.forename: Ee Cheng
authors.initials: EC
authors.lastname: Khor
authors.forename: Hao-Tian
authors.initials: HT
authors.lastname: Feng
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
authors.forename: Ming H
authors.initials: MH
authors.lastname: Zheng
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Pavlos
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D056657:Cathepsin K / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D000072159:Dynactin Complex; D004398:Dyneins / Q000378:metabolism*; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D010012:Osteogenesis / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
chemical_list: C000606361:DCTN2 protein, human; C000606365:Dctn2 protein, mouse; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D053245:RANK Ligand; C076744:cytoplasmic linker protein 170; D056657:Cathepsin K; D004398:Dyneins