title: Talin1 and Rap1 are critical for osteoclast function.
abstract: To determine talin1's role in osteoclasts, we mated TLN1(fl/fl) mice with those expressing cathepsin K-Cre (CtsK-TLN1) to delete the gene in mature osteoclasts or with lysozyme M-Cre (LysM-TLN1) mice to delete TLN1 in all osteoclast lineage cells. Absence of TLN1 impairs macrophage colony-stimulating factor (M-CSF)-stimulated inside-out integrin activation and cytoskeleton organization in mature osteoclasts. Talin1-deficient precursors normally express osteoclast differentiation markers when exposed to M-CSF and receptor activator of nuclear factor κB (RANK) ligand but attach to substrate and migrate poorly, arresting their development into mature resorptive cells. In keeping with inhibited resorption, CtsK-TLN1 mice exhibit an ∼5-fold increase in bone mass. Osteoclast-specific deletion of Rap1 (CtsK-Rap1), which promotes talin/β integrin recognition, yields similar osteopetrotic mice. The fact that the osteopetrosis of CtsK-TLN1 and CtsK-Rap1 mice is substantially more severe than that of those lacking αvβ3 is likely due to added failed activation of β1 integrins. In keeping with osteoclast dysfunction, mice in whom talin is deleted late in the course of osteoclastogenesis are substantially protected from ovariectomy-induced osteoporosis and the periarticular osteolysis attending inflammatory arthritis. Thus, talin1 and Rap1 are critical for resorptive function, and their selective inhibition in mature osteoclasts retards pathological bone loss.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
authors.forename: Takashi
authors.initials: T
authors.lastname: Izawa
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhu
authors.forename: Jean
authors.initials: J
authors.lastname: Chappel
authors.forename: Karel
authors.initials: K
authors.lastname: Otero
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Monkley
authors.forename: David R
authors.initials: DR
authors.lastname: Critchley
authors.forename: Brian G
authors.initials: BG
authors.lastname: Petrich
authors.forename: Alexei
authors.initials: A
authors.lastname: Morozov
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
authors.forename: Steven L
authors.initials: SL
authors.lastname: Teitelbaum
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D017353:Gene Deletion; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism / Q000473:pathology*; D010022:Osteopetrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D016608:Talin / Q000235:genetics / Q000378:metabolism*; D020668:rap GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D039302:Integrin alphaVbeta3; D053246:Receptor Activator of Nuclear Factor-kappa B; D016608:Talin; C496077:Tln1 protein, mouse; D016173:Macrophage Colony-Stimulating Factor; C492136:Rap1b protein, mouse; D020668:rap GTP-Binding Proteins; D020827:rap1 GTP-Binding Proteins