The protein tyrosine phosphatase Rptpζ is expressed in differentiated osteoblasts and affects bone formation in mice

Tyrosine phosphorylation of intracellular substrates is one mechanism to regulate cellular proliferation and differentiation. Protein tyrosine phosphatases (PTPs) act by dephosphorylation of substrates and thereby counteract the activity of tyrosine kinases. Few PTPs have been suggested to play a role in bone remodeling, one of them being Rptp zeta, since it has been shown to be suppressed by pleiotrophin, a heparin-binding molecule affecting bone formation, when over-expressed in transgenic mice. In a genome-wide expression analysis approach we found that Ptprz1, the gene encoding Rptp zeta, is strongly induced upon terminal differentiation of murine primary calvarial ostcoblasts. Using RT-PCR and Western Blotting we farther demonstrated that differentiated osteoblasts, in contrast to neuronal cells, specifically express the short transmembrane isoform of Rptp zeta. To uncover a potential role of Rptp zeta in bone remodeling we next analyzed the skeletal phenotype of a Rptp zeta-deficient mouse model using non-decalcified histology and histomorphometry. Compared to wildtype littermates, the Rptp zeta-deficient mice display a decreased trabecular bone volume at the age of 50 weeks, caused by a reduced bone fort-nation rate. Likewise, Rptp zeta-deficient calvarial osteoblasts analyzed ex vivo display decreased expression of osteoblast markers, indicating a cell-autonomous defect. This was confirmed by the finding that Rptp zeta-deficient osteoblasts had a diminished potential to form osteocyte-like cellular extensions on Matrigel-coated surfaces. Taken together, these data provide the first evidence for a physiological role of Rptp zeta in bone remodeling, and thus identify Rptp zeta as the first PTP regulating bone formation in vivo. (c) 2007 Elsevier Inc. All rights reserved.