Ossifying fibroma (OF) is a rare benign tumor of the craniofacial bones that can reach considerable and disfiguring dimensions if left untreated. Although the clinicopathological characteristics of OF are well established, the underlying etiology has remained largely unknown. Our work indicates that Men1—a tumor suppressor gene responsible of Multiple endocrine neoplasia type 1—is critical for OF formation and shows that mice with targeted disruption of Men1 in osteoblasts (Men1Runx2Cre) develop multifocal OF in the mandible with a 100% penetrance. Using lineage-tracing analysis, we demonstrate that loss of Men1 arrests stromal osteoprogenitors in OF at the osterix-positive pre-osteoblastic differentiation stage. Analysis of Men1-lacking stromal spindle cells isolated from OF (OF-derived MSCs (OFMSCs)) revealed a downregulation of the cyclin-dependent kinase (CDK) inhibitor Cdkn1a, consistent with an increased proliferation rate. Intriguingly, the re-expression of Men1 in Men1-deficient OFMSCs restored Cdkn1a expression and abrogated cellular proliferation supporting the tumor-suppressive role of Men1 in OF. Although our work presents the first evidence of Men1 in OF development, it further provides the first genetic mouse model of OF that can be used to better understand the molecular pathogenesis of these benign tumors and to potentially develop novel treatment strategies.
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We are grateful to the staff of the animal facilities of the University of Ulm, led by Dr Petra Kirsch and in particular to Tobias Rappold. We thank Professor Dr Volker Rasche from the Core Facility Animal MRI, Ulm University and Dr Markus Rojewsky from the Institut für Transfusionsmedizin Universitätsklinikum Ulm. We thank Dr Merle Stein and Dr Giorgio Caratti for critical reading of the manuscript. This study was supported by the Boehringer Ingelheim Foundation (to JT), Deutsche Forschungsgemeinschaft (DFG, Priority Program Immunobone 1468, Tu 220/6-1, 6-2, Collaborative Research Centre 1149, C02/INST 40/492-1, Trilateral Consortium Tu 220/12-1 to JT) and the Leibniz Graduate School of Ageing from Fritz Lipmann Institute Jena (to SL).
SL, PL, RT, MT, JK, AT, RW, SH, DB and LF performed experiments, analyzed data and wrote the paper. SV, PB, CZ and JT analyzed data and wrote the paper.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Oncogene website
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Lee, S., Liu, P., Teinturier, R. et al. Deletion of Menin in craniofacial osteogenic cells in mice elicits development of mandibular ossifying fibroma. Oncogene 37, 616–626 (2018). https://doi.org/10.1038/onc.2017.364
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