title: The Actin-Binding Protein Cofilin and Its Interaction With Cortactin Are Required for Podosome Patterning in Osteoclasts and Bone Resorption In Vivo and In Vitro.
abstract: The adhesion of osteoclasts (OCs) to bone and bone resorption require the assembly of specific F-actin adhesion structures, the podosomes, and their dense packing into a sealing zone. The OC-specific formation of the sealing zone requires the interaction of microtubule (MT) + ends with podosomes. Here, we deleted cofilin, a cortactin (CTTN)- and actin-binding protein highly expressed in OCs, to determine if it acts downstream of the MT-CTTN axis to regulate actin polymerization in podosomes. Conditional deletion of cofilin in OCs in mice, driven by the cathepsin K promoter (Ctsk-Cre), impaired bone resorption in vivo, increasing bone density. In vitro, OCs were not able to organize podosomes into peripheral belts. The MT network was disorganized, MT stability was decreased, and cell migration impaired. Active cofilin stabilizes MTs and allows podosome belt formation, whereas MT disruption deactivates cofilin via phosphorylation. Cofilin interacts with CTTN in podosomes and phosphorylation of either protein disrupts this interaction, which is critical for belt stabilization and for the maintenance of MT dynamic instability. Accordingly, active cofilin was required to rescue the OC cytoskeletal phenotype in vitro. These findings suggest that the patterning of podosomes into a sealing zone involves the dynamic interaction between cofilin, CTTN, and the MTs + ends. This interaction is critical for the functional organization of OCs and for bone resorption. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: Detina
authors.initials: D
authors.lastname: Zalli
authors.affiliation: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Neff
authors.affiliation: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nagano
authors.affiliation: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: Nah Young
authors.initials: NY
authors.lastname: Shin
authors.affiliation: Institut für Genetik, Universität Bonn, Bonn, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Witke
authors.affiliation: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Gori
authors.affiliation: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
mesh_terms: D000107:Acetylation; D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000818:Animals; D001862:Bone Resorption / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D051356:Cortactin / Q000378:metabolism*; D017353:Gene Deletion; D018390:Gene Targeting; D000073864:Histone Deacetylase 6 / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D000069261:Podosomes / Q000378:metabolism*; D011485:Protein Binding; D055114:X-Ray Microtomography
chemical_list: D051339:Actin Depolymerizing Factors; D051356:Cortactin; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6
keywords: ACTIN; BONE; COFILIN; OSTEOCLAST; PODOSOME