Paracrine osteoprotegerin and β-catenin stabilization support synovial sarcomagenesis in periosteal cells
Jared J. Barrott, … , Mario R. Capecchi, Kevin B. Jones
Jared J. Barrott, … , Mario R. Capecchi, Kevin B. Jones
Published November 20, 2017
Citation Information: J Clin Invest. 2018;128(1):207-218. https://doi.org/10.1172/JCI94955.
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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 5

Pre- and perinatal osteoblasts tolerate SS18-SSX2 expression, but render dense and disorganized skeletal phenotypes.

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Pre- and perinatal osteoblasts tolerate SS18-SSX2 expression, but render...
(A) H&E histology photomicrographs of tibiae from control and OcCre hSS2 embryos harvested 18.5 days postcoitum show dense, woven bone replacing the medullary canal in the latter. (B) Higher-power photomicrographs from the same groups show the replacement of hematopoietic progenitor cells with spindle-shaped osteoblasts in the latter. Photomicrographs of anti-EGFP IHC in a Myf5Cre hSS2 tumor (C, positive control) and bone sections from (D) an OcCre hSS2 embryo and (E) the Col1a1Cre hSS2 mouse that survived to 6 months, showing fusion expression in osteoblasts in the latter 2. (F) Micro-CT axial, coronal, and sagittal images of the tibia from a control mouse and the only surviving Col1a1Cre hSS2 mouse at 6 months of age, showing short, dense, and poorly remodeled bones in the latter. (G) H&E histology photomicrographs of cortical bone from the same mice as in F reveal contrasting lamellar control bone in the former and disorganized ossification patterns in the latter. Scale bars (A, B, G) and panel widths: 100 μm (C–F).