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Vol. 15, Issue 1, 234-244, January 2004

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Tyrosine Phosphatase Epsilon Is a Positive Regulator of Osteoclast Function in Vitro and In Vivo

Riccardo Chiusaroli ^* , Hilla Knobler  , Chen Luxenburg  , Archana Sanjay ^*, Shira Granot-Attas ^¶, Zohar Tiran ^¶, Tsuyoshi Miyazaki ^*, Alon Harmelin ^||, Roland Baron ^* #, and Ari Elson ^¶ #

^* Departments of Cell Biology and Orthopedics, Yale University School of Medicine, New Haven, Connecticut 06510; Metabolic Unit, Kaplan Medical Center, Rehovot, Israel; Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel; ^¶ Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel; and ^|| Department of Veterinary Resources, The Weizmann Institute of Science, Rehovot 76100, Israel

Submitted April 6, 2003; Revised August 31, 2003; Accepted September 9, 2003
Monitoring Editor: Mary Beckerle

Protein tyrosine phosphorylation is a major regulator of bone metabolism. Tyrosine phosphatases participate in regulating phosphorylation, but roles of specific phosphatases in bone metabolism are largely unknown. We demonstrate that young (<12 weeks) female mice lacking tyrosine phosphatase epsilon (PTP) exhibit increased trabecular bone mass due to cell-specific defects in osteoclast function. These defects are manifested in vivo as reduced association of osteoclasts with bone and as reduced serum concentration of C-terminal collagen telopeptides, specific products of osteoclast-mediated bone degradation. Osteoclast-like cells are generated readily from PTP-deficient bone-marrow precursors. However, cultures of these cells contain few mature, polarized cells and perform poorly in bone resorption assays in vitro. Podosomes, structures by which osteoclasts adhere to matrix, are disorganized and tend to form large clusters in these cells, suggesting that lack of PTP adversely affects podosomal arrangement in the final stages of osteoclast polarization. The gender and age specificities of the bone phenotype suggest that it is modulated by hormonal status, despite normal serum levels of estrogen and progesterone in affected mice. Stimulation of bone resorption by RANKL and, surprisingly, Src activity and Pyk2 phosphorylation are normal in PTP-deficient osteoclasts, indicating that loss of PTP does not cause widespread disruption of these signaling pathways. These results establish PTP as a phosphatase required for optimal structure, subcellular organization, and function of osteoclasts in vivo and in vitro.

Abbreviations used: PTP, protein tyrosine phosphatase; cyt-PTP, nonreceptor form of PTP; Ptpre-/-; genetically lacking PTP; OCL, osteoclast-like cell.

These authors contributed equally to this work.

^# Corresponding authors. E-mail addresses: roland.baron{at}yale.edu; ari.elson{at}weizmann.ac.il.

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