The protein tyrosine phosphatase Rptpzeta 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 Rptpzeta, 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 Rptpzeta, is strongly induced upon terminal differentiation of murine primary calvarial osteoblasts. Using RT-PCR and Western Blotting we further demonstrated that differentiated osteoblasts, in contrast to neuronal cells, specifically express the short transmembrane isoform of Rptpzeta. To uncover a potential role of Rptpzeta in bone remodeling we next analyzed the skeletal phenotype of a Rptpzeta-deficient mouse model using non-decalcified histology and histomorphometry. Compared to wildtype littermates, the Rptpzeta-deficient mice display a decreased trabecular bone volume at the age of 50 weeks, caused by a reduced bone formation rate. Likewise, Rptpzeta-deficient calvarial osteoblasts analyzed ex vivo display decreased expression of osteoblast markers, indicating a cell-autonomous defect. This was confirmed by the finding that Rptpzeta-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 Rptpzeta in bone remodeling, and thus identify Rptpzeta as the first PTP regulating bone formation in vivo.
Schinke
T
T
Department of Trauma, Hand, and Reconstructive Surgery, University Medical Center Hamburg Eppendorf, Hamburg 20246, Germany.
Gebauer
M
M
Schilling
A F
AF
Lamprianou
S
S
Priemel
M
M
Mueldner
C
C
Neunaber
C
C
Streichert
T
T
Ignatius
A
A
Harroch
S
S
Amling
M
M
D016475:3T3 Cells; D000818:Animals; D001842:Bone and Bones / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000201:enzymology*; D010012:Osteogenesis / Q000502:physiology*; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000235:genetics / Q000378:metabolism*; D012863:Skeleton
D020033:Protein Isoforms; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5