title: Type I phosphotidylinosotol 4-phosphate 5-kinase γ regulates osteoclasts in a bifunctional manner.
abstract: Type 1 phosphotidylinosotol-4 phosphate 5 kinase γ (PIP5KIγ) is central to generation of phosphotidylinosotol (4,5)P(2) (PI(4,5)P(2)). PIP5KIγ also participates in cytoskeletal organization by delivering talin to integrins, thereby enhancing their ligand binding capacity. As the cytoskeleton is pivotal to osteoclast function, we hypothesized that absence of PIP5KIγ would compromise their resorptive capacity. Absence of the kinase diminishes PI(4,5) abundance and desensitizes precursors to RANK ligand-stimulated differentiation. Thus, PIP5KIγ(-/-) osteoclasts are reduced in number in vitro and confirm physiological relevance in vivo. Despite reduced numbers, PIP5KIγ(-/-) osteoclasts surprisingly have normal cytoskeletons and effectively resorb bone. PIP5KIγ overexpression, which increases PI(4,5)P(2), also delays osteoclast differentiation and reduces cell number but in contrast to cells lacking the kinase, its excess disrupts the cytoskeleton. The cytoskeleton-disruptive effects of excess PIP5KIγ reflect its kinase activity and are independent of talin recognition. The combined arrested differentiation and disorganized cytoskeleton of PIP5KIγ-transduced osteoclasts compromises bone resorption. Thus, optimal PIP5KIγ and PI(4,5)P(2) expression, by osteoclasts, are essential for skeletal homeostasis.
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhu
authors.forename: Jean C
authors.initials: JC
authors.lastname: Chappel
authors.forename: Fong-Fu
authors.initials: FF
authors.lastname: Hsu
authors.forename: John
authors.initials: J
authors.lastname: Turk
authors.forename: Rajeev
authors.initials: R
authors.lastname: Aurora
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Hyrc
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Broekelmann
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mecham
authors.forename: Steven L
authors.initials: SL
authors.lastname: Teitelbaum
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
mesh_terms: D000818:Animals; D001692:Biological Transport; D001862:Bone Resorption; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D015971:Gene Expression Regulation, Enzymologic; D008024:Ligands; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000166:cytology* / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods
chemical_list: D008024:Ligands; D010716:Phosphatidylinositols; D053245:RANK Ligand; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D002118:Calcium