title: The Protein Tyrosine Phosphatase Rptpζ Suppresses Osteosarcoma Development in Trp53-Heterozygous Mice.
abstract: Osteosarcoma (OS), a highly aggressive primary bone tumor, belongs to the most common solid tumors in growing children. Since specific molecular targets for OS treatment remain to be identified, surgical resection combined with multimodal (neo-)adjuvant chemotherapy is still the only way to help respective individuals. We have previously identified the protein tyrosine phosphatase Rptpζ as a marker of terminally differentiated osteoblasts, which negatively regulates their proliferation in vitro. Here we have addressed the question if Rptpζ can function as a tumor suppressor protein inhibiting OS development in vivo. We therefore analyzed the skeletal phenotype of mice lacking Ptprz1, the gene encoding Rptpζ on a tumor-prone genetic background, i.e. Trp53-heterozygosity. By screening a large number of 52 week old Trp53-heterozygous mice by contact radiography we found that Ptprz1-deficiency significantly enhanced OS development with 19% of the mice being affected. The tumors in Ptprz1-deficient Trp53-heterozygous mice were present in different locations (spine, long bones, ribs), and their OS nature was confirmed by undecalcified histology. Likewise, cell lines derived from the tumors were able to undergo osteogenic differentiation ex vivo. A comparison between Ptprz1-heterozygous and Ptprz1-deficient cultures further revealed that the latter ones displayed increased proliferation, a higher abundance of tyrosine-phosphorylated proteins and resistance towards the influence of the growth factor Midkine. Our findings underscore the relevance of Rptpζ as an attenuator of proliferation in differentiated osteoblasts and raise the possibility that activating Rptpζ-dependent signaling could specifically target osteoblastic tumor cells.
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg Eppendorf, Hamburg 20246, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Baldauf
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg Eppendorf, Hamburg 20246, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Jeschke
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg Eppendorf, Hamburg 20246, Germany.
authors.forename: Vincent
authors.initials: V
authors.lastname: Kanbach
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg Eppendorf, Hamburg 20246, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Catala-Lehnen
authors.affiliation: Bone Tumor Reference Center at the Institute of Pathology, University Hospital Basel, Basel 4031, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Baumhoer
authors.affiliation: Research Institute Children's Cancer Center and Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Hamburg 20246, Germany.
authors.forename: Helwe
authors.initials: H
authors.lastname: Gerull
authors.affiliation: Research Institute Children's Cancer Center and Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Hamburg 20246, Germany.
authors.forename: Sophia
authors.initials: S
authors.lastname: Buhs
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg Eppendorf, Hamburg 20246, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.affiliation: Research Institute Children's Cancer Center and Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Hamburg 20246, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nollau
authors.affiliation: Department of Neuroscience, Institute Pasteur, Paris 75624, France.
authors.forename: Sheila
authors.initials: S
authors.lastname: Harroch
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg Eppendorf, Hamburg 20246, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
mesh_terms: D000818:Animals; D015415:Biomarkers; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression; D016158:Genes, p53; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000078792:Midkine; D009154:Mutation; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000235:genetics; D012516:Osteosarcoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D036341:Intercellular Signaling Peptides and Proteins; C582105:Mdk protein, mouse; D000078792:Midkine; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5