title: WASp deficiency in mice results in failure to form osteoclast sealing zones and defects in bone resorption.
abstract: No defects related to deficiency of the Wiskott-Aldrich Syndrome protein (WASp) have been described in osteoclasts. Here we show that there are significant morphologic and functional abnormalities. WASp-null cells spread over a much larger surface area and are highly polykaryotic. In their migratory phase, normal cells assemble clusters of podosomes behind their leading edges, whereas during the bone resorptive phase multiple podosomes are densely aggregated in well-defined actin rings forming the sealing zone. In comparison, WASp-null osteoclasts in either phase are markedly depleted of podosomes. On bone surfaces, this results in a failure to form actin rings at sealing zones. Complementation of WASp-null osteoclasts with an enhanced green fluorescent protein (eGFP)-WASp fusion protein restores normal cytoarchitecture. These structural disturbances translate into abnormal patterns of bone resorption both in vitro on bone slices and in vivo. Although physiologic steady-state levels of bone resorption are maintained, a major impairment is observed when WASp-null animals are exposed to a resorptive challenge. Our results provide clear evidence that WASp is a critical component of podosomes in osteoclasts and indicate a nonredundant role for WASp in the dynamic organization of these actin structures during bone resorption.
authors.affiliation: The Randall Centre for Molecular Mechanisms of Cell Function, New Hunt's House, King's College London, Guy's Campus, London, United Kingdom. yolanda.calle@kcl.ac.uk
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Calle
authors.forename: Gareth E
authors.initials: GE
authors.lastname: Jones
authors.forename: Chris
authors.initials: C
authors.lastname: Jagger
authors.forename: Karen
authors.initials: K
authors.lastname: Fuller
authors.forename: Mike P
authors.initials: MP
authors.lastname: Blundell
authors.forename: Jade
authors.initials: J
authors.lastname: Chow
authors.forename: Tim
authors.initials: T
authors.lastname: Chambers
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
mesh_terms: D008841:Actin Cytoskeleton; D000818:Animals; D016723:Bone Remodeling; D001862:Bone Resorption; D022081:Cell Surface Extensions; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010010:Osteoclasts / Q000378:metabolism / Q000648:ultrastructure*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic; D051316:Wiskott-Aldrich Syndrome Protein
chemical_list: D011506:Proteins; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein