Paracrine osteoprotegerin and β-catenin stabilization support synovial sarcomagenesis in periosteal cells
Jared J. Barrott, Benjamin E. Illum, Huifeng Jin, Matthew L. Hedberg, Yanliang Wang, Allie Grossmann, Malay Haldar, Mario R. Capecchi, Kevin B. Jones
Jared J. Barrott, Benjamin E. Illum, Huifeng Jin, Matthew L. Hedberg, Yanliang Wang, Allie Grossmann, Malay Haldar, Mario R. Capecchi, Kevin B. Jones
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Research Article Development Oncology

Paracrine osteoprotegerin and β-catenin stabilization support synovial sarcomagenesis in periosteal cells

Abstract

Synovial sarcoma (SS) is an aggressive soft-tissue sarcoma that is often discovered during adolescence and young adulthood. Despite the name, synovial sarcoma does not typically arise from a synoviocyte but instead arises in close proximity to bones. Previous work demonstrated that mice expressing the characteristic SS18-SSX fusion oncogene in myogenic factor 5–expressing (Myf5-expressing) cells develop fully penetrant sarcomagenesis, suggesting skeletal muscle progenitor cell origin. However, Myf5 is not restricted to committed myoblasts in embryos but is also expressed in multipotent mesenchymal progenitors. Here, we demonstrated that human SS and mouse tumors arising from SS18-SSX expression in the embryonic, but not postnatal, Myf5 lineage share an anatomic location that is frequently adjacent to bone. Additionally, we showed that SS can originate from periosteal cells expressing SS18-SSX alone and from preosteoblasts expressing the fusion oncogene accompanied by the added stabilization of β-catenin, which is a common secondary change in SS. Expression and secretion of the osteoclastogenesis inhibitory factor osteoprotegerin enabled early growth of SS18-SSX2–transformed cells, indicating a paracrine link between the bone and synovial sarcomagenesis. These findings explain the skeletal contact frequently observed in human SS and may provide alternate means of enabling SS18-SSX–driven oncogenesis in cells as differentiated as preosteoblasts.

Authors

Jared J. Barrott, Benjamin E. Illum, Huifeng Jin, Matthew L. Hedberg, Yanliang Wang, Allie Grossmann, Malay Haldar, Mario R. Capecchi, Kevin B. Jones

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Figure 9

β-Catenin stabilization enables synovial sarcomagenesis from preosteoblasts.

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β-Catenin stabilization enables synovial sarcomagenesis from preosteobla...
(A) Kaplan-Meier plot of tumorigenesis among OsxCreERT mice bearing hSS2, Ctnnb1ex3fl, or both and that received tamoxifen at 2 weeks of age (solid line; n = 7; log rank test vs. control Z score = 3.15 and P =0.0016) or 4 weeks of age (dotted line; n = 7; Z score = 3.85 and P < 0.001). (B and C) Posteroanterior radiographs of OsxCreERT Ctnnb1ex3fl mice at 12 months of age, showing increased skeletal density, especially in apparently residual primary spongiosal regions, now in the metadiaphysis (open arrowhead). (D and E) OsxCreERT hSS2 Ctnnb1ex3fl mice at age 12 weeks of age with the same findings (open arrowhead) plus periosteal reactive bone and soft-tissue shadows (solid black arrowheads). (F) Gross dissection and (G) GFP fluorescence images show multiple periscapular tumors (solid black arrowheads) in a 12-week-old OsxCreERT hSS2 Ctnnb1ex3fl mouse. (H) Scapular H&E photomicrographs from a control mouse and (I) a OsxCreERT hSS2 Ctnnb1ex3fl mouse, the latter showing tumors (solid black arrowheads). (J) Photomicrographs of H&E staining of femur sagittal sections from a control mouse and (K) a OsxCreERT Ctnnb1ex3fl mouse, the latter showing dense, unremodeled primary spongiosa (open arrowhead). (L) Graph of fractions of trabecular bone area in metaphyseal femora from 12-week-old OsxCreERT Ctnnb1ex3fl/WT or Ctnnb1WT/WT mice (bars depict the mean; n = 7 femora; P < 0.0001, by 2-tailed Student’s t test). (M) Graph of TRAP+ osteoclasts (OCs) per high-power field (HPF) (bars depict the mean; n = 4 femora per group and ≥5 areas counted per femur; P < 0.0001, by 2-tailed Student’s t test). Scale bars: 100 um.