Central giant cell granulomas of the jaws stromal cells harbour mutations and have osteogenic differentiation capacity, in vivo and in vitro

• Published in: Journal of oral pathology & medicine Vol. 51; no. 2; pp. 206 - 216
• Main Authors: Miguita, Lucyene, de Souza, Juliana Cristina, Bastos, Victor Coutinho, Pereira, Nubia Braga, de Freitas, Raphaela Alvarenga Braga, Guimarães, Leticia Martins, de Avelar, Gleide Fernandes, Andrade, Luciana Oliveira, Dutra, Walderez Ornelas, Nunes, Fábio Daumas, Castro, Wagner Henriques, de Lacerda, Julio Cesar Tanos, Reis, Amanda Maria Sena, Bernardes, Vanessa Fátima, Diniz, Marina Gonçalves, Gomez, Ricardo Santiago, Gomes, Carolina Cavalieri
• Format: Journal Article
• Language: English
• Published: Denmark Wiley Subscription Services, Inc 01.02.2022
• Subjects: Alkaline Phosphatase; Bone cancer; Bone growth; bone tumour; Cbfa-1 protein; CD14 antigen; Cell culture; Cell Differentiation; Cells, Cultured; Cytochemistry; Fibroblast growth factor receptor 1; Flow cytometry; Gene expression; genetics; Giant cells; Granuloma, Giant Cell - genetics; Granulomas; Humans; Jaw; Lasers; Leukocytes (mononuclear); Macrophages; Mesenchymal Stem Cells; Mesenchyme; Monocytes; Mutation; mutations; Osteocalcin; Osteogenesis; Osteogenesis - genetics; Osteoid; Osteolysis; Osteopontin; patient‐derived xenograft; Stromal Cells; Tumors; Xenografts; genetics; mutations; osteogenesis; bone tumour; patient-derived xenograft
• ISSN: 0904-2512; 1600-0714
• DOI: 10.1111/jop.13274

Background Central giant cell granulomas (CGCG) of the jaws are osteolytic lesions that may behave aggressively and respond poorly to surgery. Microscopically, in addition to giant cells, there is a mononuclear cell population composed of macrophage/monocytic cells and spindle‐shaped cells of mesenchymal origin. Seventy two percent of these tumours harbour mutually exclusive TRPV4, KRAS and FGFR1 mutations. We aimed to assess the mutational status of mononuclear and giant cells and the osteogenic potential of stromal cells in vitro and in vivo. Methods and Results We screened CGCG for signature mutations and used laser‐capture microdissection to demonstrate that the mutations are restricted to the mononuclear cells. Additionally, we established CGCG primary cell culture and observed that the cells retained the mutations throughout passages. By flow cytometry, we observed predominance of CD14−CD51−CD61− cells, consistent with the expected profile for stromal cells. Considering the mesenchymal origin of stromal cells, we assessed the osteogenic differentiation potential of CGCG cells in culture by cytochemistry (von Kossa and alizarin red staining), alkaline phosphatase (ALP) activity assay and gene expression of osteogenic markers. CGCG cells presented self‐capacity to increase ALP levels in a time‐dependent manner and under osteogenic induction presented increasing number of calcium deposits, and overall higher expression of osteocalcin, RUNX2, ALPL and osteopontin than cells without osteogenic induction. A patient‐derived xenograft model for CGCG was established, and osteoid material deposition was observed. Conclusion Collectively, the results confirm that the signature mutations are restricted to stromal cells in CGCG, and the in vitro and in vivo results support that these cells have the capacity to differentiate into osteoblasts, in line with the bone formation often observed in the stroma of these lesions.