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Originally published In Press as doi:10.1074/jbc.M008368200 on December 1, 2000

J. Biol. Chem., Vol. 276, Issue 10, 7484-7492, March 9, 2001
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Inhibition of Osteoclast Function by Adenovirus Expressing Antisense Protein-tyrosine Kinase 2*

Le T. DuongDagger §, Ichiro NakamuraDagger , Päivi T. Lakkakorpi, Lorraine LipfertDagger , Andrew J. Bett||, and Gideon A. RodanDagger

From the Departments of Dagger  Bone Biology and Osteoporosis and || Virus and Cell Biology, Merck Research Laboratories, West Point, Pennsylvania 19486 and the  Institute of Biomedicine, Department of Anatomy, University of Turku, FIN-20520 Turku, Finland

Osteoclast activation is initiated by adhesion to bone, cytoskeletal rearrangement, formation of the sealing zone, and formation of the polarized ruffled membrane. Previous findings suggest that protein-tyrosine kinase 2 (PYK2), a cytoplasmic kinase related to focal adhesion kinase, participates in these events. This study examines the role of PYK2 in adhesion-mediated signaling and osteoclast function, using PYK2 antisense. We produced a recombinant adenovirus containing a 300-base pair reversed 5'-coding region of PYK2 and used full-length PYK2 as a control. Murine osteoclast-like cells or their mononuclear precursors were generated in a co-culture of bone marrow and osteoblasts. Infection with antisense adenovirus significantly reduced the expression of endogenous PYK2 protein relative to uninfected cells or to cells infected with sense PYK2 and caused: 1) a reduction in osteoclast formation in vitro; 2) inhibition of cell spreading and of actin ring formation in osteoclasts plated on glass or bone and of attachment and spreading of osteoclast precursors plated on vitronectin; 3) inhibition of bone resorption in vitro; 4) marked reduction in p130Cas tyrosine phosphorylation; and 5) no change in alpha vbeta 3 integrin expression or c-Src tyrosine phosphorylation. Taken together, these findings support the hypothesis that PYK2 plays a central role in the adhesion-dependent cytoskeletal organization and sealing zone formation required for osteoclastic bone resorption.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Dept. of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, PA 19486.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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