INSERM, UMRS 1138 Equipe 5, Laboratoire de Physiopathologie Orale Moléculaire, Centre de Recherche de Cordeliers, 75006, Paris, France.
Université Paris Descartes, 75006, Paris, France.
Orphanet J Rare Dis. 2018 Sep 20;13(1):166. doi: 10.1186/s13023-018-0907-2.
Cherubism is a rare autosomal dominant disorder of the jaws caused by mutation of the SH3BP2 gene. The bone is replaced by a fibrous granuloma containing multinucleated giant cells. Cells of the cherubism granuloma have never been systematically analyzed. Hence, the aim of this study was to characterize the cells in human cherubism granulomas, to determine the osteoclastic characteristics of the multinucleated giant cells and to investigate the potential role of TNF-α in human cherubism.
Seven granulomas were analyzed in pathology, molecular biology and immunohistochemistry. Granulomas were composed mainly of macrophages or osteoclasts within a fibroblastic tissue, with few lymphoid cells. Myeloid differentiation and nuclear NFATc1 localization were both associated with disease aggressiveness. OPG and RANKL immunohistochemical expression was unexpected in our specimens. Five granuloma cells were cultured in standard and osteoclastogenic media. In culture, cherubism cells were able to differentiate into active osteoclasts, in both osteoclastogenic and standard media. IL-6 was the major cytokine present in the culture supernatants.
Multinucleated giant cells from cherubism granulomas are CD68 positive cells, which differentiate into macrophages in non-aggressive cherubism and into osteoclasts in aggressive cherubism, stimulated by the NFATc1 pathway. This latter differentiation appears to involve a disturbed RANK-L/RANK/OPG pathway and be less TNF-α dependent than the cherubism mouse model.
cherubism 是一种罕见的常染色体显性遗传颌骨疾病，由 SH3BP2 基因突变引起。骨骼被纤维性肉芽肿取代，其中包含多核巨细胞。 cherubism 肉芽肿中的细胞从未被系统地分析过。因此，本研究的目的是分析人 cherubism 肉芽肿中的细胞，确定多核巨细胞的破骨细胞特征，并研究 TNF-α 在人 cherubism 中的潜在作用。
在病理学、分子生物学和免疫组织化学方面分析了 7 个肉芽肿。肉芽肿主要由成纤维组织中的巨噬细胞或破骨细胞组成，淋巴细胞较少。髓样分化和核 NFATc1 定位都与疾病的侵袭性有关。在我们的标本中，OPG 和 RANKL 的免疫组织化学表达出乎意料。将 5 个肉芽肿细胞在标准和破骨细胞生成培养基中培养。在培养中， cherubism 细胞能够在破骨细胞生成和标准培养基中分化为活性破骨细胞。IL-6 是培养上清液中主要的细胞因子。
cherubism 肉芽肿中的多核巨细胞是 CD68 阳性细胞，在非侵袭性 cherubism 中分化为巨噬细胞，在侵袭性 cherubism 中分化为破骨细胞，受 NFATc1 途径的刺激。这种分化似乎涉及到 RANK-L/RANK/OPG 途径的紊乱，并且比 cherubism 小鼠模型更不依赖 TNF-α。
