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A more recent version of this article appeared on January 1, 2004
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Submitted on April 6, 2003
Revised on August 31, 2003
Accepted on September 9, 2003
1 Departments of Cell Biology and Orthopedics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA
2 Metabolic Unit, Kaplan Medical Center, Rehovot, Israel
3 Departments of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel
4 Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel
5 Department of Veterinary Resources, The Weizmann Institute of Science, Rehovot 76100, Israel
* Corresponding author. E-mail address: ari.elson{at}weizmann.ac.il.
* Corresponding author. E-mail address: ari.elson{at}weizmann.ac.il.
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 wk) 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.
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