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
| Autor: | Walter Witke, Nah-Young Shin, Kenichi Nagano, Roland Baron, Detina Zalli, Lynn Neff, Francesca Gori |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Podosome Endocrinology Diabetes and Metabolism Osteoclasts macromolecular substances Histone Deacetylase 6 environment and public health Microtubules Bone resorption Article 03 medical and health sciences Mice 0302 clinical medicine Osteoclast medicine Animals Humans Orthopedics and Sports Medicine Actin-binding protein Bone Resorption Phosphorylation Cytoskeleton Actin biology Acetylation X-Ray Microtomography Cofilin Cell biology 030104 developmental biology medicine.anatomical_structure Phenotype Actin Depolymerizing Factors 030220 oncology & carcinogenesis Gene Targeting Podosomes biology.protein Cortactin Gene Deletion Protein Binding |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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