title: Vinculin regulates osteoclast function.
abstract: Osteoclastic bone resorption depends upon the cell's ability to organize its cytoskeleton. Because vinculin (VCL) is an actin-binding protein, we asked whether it participates in skeletal degradation. Thus, we mated VCL(fl/fl) mice with those expressing cathepsin K-Cre (CtsK-VCL) to delete the gene in mature osteoclasts or lysozyme M-Cre (LysM-VCL) to target all osteoclast lineage cells. VCL-deficient osteoclasts differentiate normally but, reflecting cytoskeletal disorganization, form small actin rings and fail to effectively resorb bone. In keeping with inhibited resorptive function, CtsK-VCL and LysM-VCL mice exhibit a doubling of bone mass. Despite cytoskeletal disorganization, the capacity of VCL(-/-) osteoclastic cells to normally phosphorylate c-Src in response to αvβ3 integrin ligand is intact. Thus, integrin-activated signals are unrelated to the means by which VCL organizes the osteoclast cytoskeleton. WT VCL completely rescues actin ring formation and bone resorption, as does VCL(P878A), which is incapable of interacting with Arp2/3. As expected, deletion of the VCL tail domain (VCL(1-880)), which binds actin, does not normalize VCL(-/-) osteoclasts. The same is true regarding VCL(I997A), which also prevents VCL/actin binding, and VCL(A50I) and VCL(811-1066), both of which arrest talin association. Thus, VCL binding talin, but not Arp2/3, is critical for osteoclast function, and its selective inhibition retards physiological bone loss.
authors.affiliation: From the Departments of Pathology and Immunology and.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Fukunaga
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
authors.forename: Julia T
authors.initials: JT
authors.lastname: Warren
authors.forename: Steven L
authors.initials: SL
authors.lastname: Teitelbaum
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000235:genetics / Q000378:metabolism; D000199:Actins / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000081247:CSK Tyrosine-Protein Kinase; D003599:Cytoskeleton / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016608:Talin / Q000235:genetics / Q000378:metabolism; D016596:Vinculin / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D016608:Talin; D016596:Vinculin; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases
keywords: Bone; Cell Biology; Cytoskeleton; Integrins; Osteoclast; Vinculin