title: Regulation of osteoclast structure and function by FAK family kinases.
abstract: Osteoclasts are highly specialized cells that resorb bone and contribute to bone remodeling. Diseases such as osteoporosis and osteolytic bone metastasis occur when osteoclast-mediated bone resorption takes place in the absence of concurrent bone synthesis. Considerable effort has been placed on identifying molecules that regulate the bone resorption activity of osteoclasts. To this end, we investigated unique and overlapping functions of members of the FAK family (FAK and Pyk2) in osteoclast functions. With the use of a conditional knockout mouse model, in which FAK is selectively targeted for deletion in osteoclast precursors (FAK(Δmyeloid)), we found that loss of FAK resulted in reduced bone resorption by osteoclasts in vitro, coincident with impaired signaling through the CSF-1R. However, bone architecture appeared normal in FAK(Δmyeloid) mice, suggesting that Pyk2 might functionally compensate for reduced FAK levels in vivo. This was supported by data showing that podosome adhesion structures, which are essential for bone degradation, were significantly more impaired in osteoclasts when FAK and Pyk2 were reduced than when either molecule was depleted individually. We conclude that FAK contributes to cytokine signaling and bone resorption in osteoclasts and partially compensates for the absence of Pyk2 to maintain proper adhesion structures in these cells.
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Brianne J
authors.initials: BJ
authors.lastname: Ray
authors.forename: Keena
authors.initials: K
authors.lastname: Thomas
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Huang
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gutknecht
authors.forename: Edward A
authors.initials: EA
authors.lastname: Botchwey
authors.forename: Amy H
authors.initials: AH
authors.lastname: Bouton
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000201:enzymology* / Q000473:pathology; D001842:Bone and Bones / Q000201:enzymology / Q000473:pathology; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000201:enzymology* / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; C496051:Ptk2 protein, mouse; C496053:Ptk2b protein, mouse