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Investigating global gene expression changes in a murine model of cherubism
Bone ( IF 4.1 ) Pub Date : 2020-06-01 , DOI: 10.1016/j.bone.2020.115315
Tulika Sharma 1 , Justin Cotney 2 , Vijender Singh 3 , Archana Sanjay 4 , Ernst J Reichenberger 1 , Yasuyoshi Ueki 5 , Peter Maye 1
Affiliation  

Cherubism is a rare genetic disorder caused primarily by mutations in SH3BP2 resulting in excessive bone resorption and fibrous tissue overgrowth in the lower portions of the face. Bone marrow derived cell cultures derived from a murine model of cherubism display poor osteogenesis and spontaneous osteoclast formation. To develop a deeper understanding for the potential underlying mechanisms contributing to these phenotypes in mice, we compared global gene expression changes in hematopoietic and mesenchymal cell populations between cherubism and wild type mice. In the hematopoietic population, not surprisingly, upregulated genes were significantly enriched for functions related to osteoclastogenesis. However, these upregulated genes were also significantly enriched for functions associated with inflammation including arachidonic acid/prostaglandin signaling, regulators of coagulation and autoinflammation, extracellular matrix remodeling, and chemokine expression. In the mesenchymal population, we observed down regulation of osteoblast and adventitial reticular cell marker genes. Regulators of BMP and Wnt pathway associated genes showed numerous changes in gene expression, likely implicating the down regulation of BMP signaling and possibly the activation of certain Wnt pathways. Analyses of the cherubism derived mesenchymal population also revealed interesting changes in gene expression related to inflammation including the expression of distinct granzymes, chemokines, and sulfotransferases. These studies reveal complex changes in gene expression elicited from a cherubic mutation in Sh3bp2 that are informative to the mechanisms responding to inflammatory stimuli and repressing osteogenesis. The outcomes of this work are likely to have relevance not only to cherubism, but other inflammatory conditions impacting the skeleton.

中文翻译:

调查小天使小鼠模型中的全球基因表达变化

Cherubism 是一种罕见的遗传性疾病,主要由 SH3BP2 突变导致面部下部骨吸收过度和纤维组织过度生长。源自小天使小鼠模型的骨髓衍生细胞培养物显示出较差的成骨和自发性破骨细胞形成。为了更深入地了解导致小鼠这些表型的潜在潜在机制,我们比较了小天使和野生型小鼠之间造血和间充质细胞群的全局基因表达变化。在造血群体中,毫不奇怪,上调基因显着富集与破骨细胞生成相关的功能。然而,这些上调基因还显着丰富了与炎症相关的功能,包括花生四烯酸/前列腺素信号传导、凝血和自身炎症调节剂、细胞外基质重塑和趋化因子表达。在间充质细胞群中,我们观察到成骨细胞和外膜网状细胞标记基因的下调。BMP 和 Wnt 通路相关基因的调节剂显示出基因表达的许多变化,可能暗示 BMP 信号传导的下调和某些 Wnt 通路的激活。对小天使衍生的间充质群体的分析还揭示了与炎症相关的基因表达的有趣变化,包括不同颗粒酶、趋化因子和磺基转移酶的表达。这些研究揭示了由 Sh3bp2 中的天使突变引起的基因表达的复杂变化,这些变化对响应炎症刺激和抑制成骨的机制提供了信息。这项工作的结果可能不仅与小天使有关,而且与影响骨骼的其他炎症状况有关。
更新日期:2020-06-01
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