title: Kindlin-3-mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption.
abstract: The blood cell-specific kindlin-3 protein is required to activate leukocyte and platelet integrins. In line with this function, mutations in the KINDLIN-3 gene in man cause immunodeficiency and severe bleeding. Some patients also suffer from osteopetrosis, but the underlying mechanism leading to abnormal bone turnover is unknown. Here we show that kindlin-3-deficient mice develop severe osteopetrosis because of profound adhesion and spreading defects in bone-resorbing osteoclasts. Mechanistically, loss of kindlin-3 impairs the activation of β1, β2, and β3 integrin classes expressed on osteoclasts, which in turn abrogates the formation of podosomes and sealing zones required for bone resorption. In agreement with these findings, genetic ablation of all integrin classes abolishes the development of podosomes, mimicking kindlin-3 deficiency. Although loss of single integrin classes gives rise to podosomes, their resorptive activity is impaired. These findings show that osteoclasts require their entire integrin repertoire to be regulated by kindlin-3 to orchestrate bone homeostasis.
authors.affiliation: Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Schmidt
authors.forename: Inaam
authors.initials: I
authors.lastname: Nakchbandi
authors.forename: Raphael
authors.initials: R
authors.lastname: Ruppert
authors.forename: Nina
authors.initials: N
authors.lastname: Kawelke
authors.forename: Michael W
authors.initials: MW
authors.lastname: Hess
authors.forename: Kristian
authors.initials: K
authors.lastname: Pfaller
authors.forename: Pierre
authors.initials: P
authors.lastname: Jurdic
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
authors.forename: Markus
authors.initials: M
authors.lastname: Moser
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000235:genetics* / Q000378:metabolism; D018821:CD18 Antigens / Q000378:metabolism; D002454:Cell Differentiation; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000502:physiology; D019012:Integrin beta1 / Q000378:metabolism; D039661:Integrin beta3 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D010022:Osteopetrosis / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D018821:CD18 Antigens; D003598:Cytoskeletal Proteins; D019012:Integrin beta1; D039661:Integrin beta3; D036341:Intercellular Signaling Peptides and Proteins; C527818:kindlin-3 protein, mouse