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Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2^–/– mice

¹ Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06511
² Departments of Cell Biology and Orthopaedics, Yale University School of Medicine, New Haven, CT 06511
³ Department of Hard Tissue Engineering, Section of Pharmacology, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549, Japan

Correspondence to Joseph Schlessinger: joseph.schlessinger{at}yale.edu; or Roland Baron: roland.baron{at}yale.edu.

The protein tyrosine kinase Pyk2 is highly expressed in osteoclasts, where it is primarily localized in podosomes. Deletion of Pyk2 in mice leads to mild osteopetrosis due to impairment in osteoclast function. Pyk2-null osteoclasts were unable to transform podosome clusters into a podosome belt at the cell periphery; instead of a sealing zone only small actin rings were formed, resulting in impaired bone resorption. Furthermore, in Pyk2-null osteoclasts, Rho activity was enhanced while microtubule acetylation and stability were significantly reduced. Rescue experiments by ectopic expression of wild-type or a variety of Pyk2 mutants in osteoclasts from Pyk2^–/– mice have shown that the FAT domain of Pyk2 is essential for podosome belt and sealing zone formation as well as for bone resorption. These experiments underscore an important role of Pyk2 in microtubule-dependent podosome organization, bone resorption, and other osteoclast functions.

N.A. Sims' present address is St. Vincent's Institute, Fitzroy VIC 3065, Victoria, Australia.

K. Aoki's present address is Department of Hard Tissue Engineering, Section of Pharmacology, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549, Japan.

A. Sanjay's present address is Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140.

Abbreviations used in this paper: FAT, focal adhesion targeting; RBD, Rho binding domain.

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