SOST Gene Inhibits Osteogenesis from Adipose-Derived Mesenchymal Stem Cells by Inducing Th17 Cell Differentiation
SOST Gene Inhibits Osteogenesis from Adipose-Derived Mesenchymal Stem Cells by Inducing Th17 Cell Differentiation
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SOST 基因通过诱导 Th17 细胞分化抑制脂肪间充质干细胞成骨
DOI：
10.1159/000491971
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发表时间：
2018-01-01
影响因子：
--
通讯作者：
Chen, Jinyu
中科院分区：
文献类型：
--
作者：
You, Li;Chen, Lin;Chen, Jinyu
背景/目标：绝经后骨质疏松症被认为是一种自身免疫和炎症过程，IL-17在骨量丢失中起重要作用。硬化蛋白（SOST）通过抑制Wnt信号通路作为骨形成的负调节剂。它也是骨骼和免疫系统之间相互作用的介质。然而，很少有研究探讨SOST基因在T辅助细胞17（Th 17）分化中的作用。研究方法：分离脂肪干细胞（Adipose-derived stem cells，ADSCs），分别转染pcDNA 3-SOST和shSOST，与外周血单个核细胞分离的CD 4 + T细胞共培养。在此共培养模型中，通过western blot、细胞内和核内染色、ELISA和实时定量PCR检测Th 17和调节性T（Treg）细胞的分化、脂肪生成和成骨。结果：SOST基因可促进ADSCs分泌IL-6和TGF-β。SOST基因可增加ADSCs与CD 4 + T细胞共培养后的CD 4 +IL-17+细胞数，并可增加IL-17和RORγ的水平。但CD 4 + CD 25 + Foxp 3+细胞数量减少，同时伴有IL-10和Foxp 3表达减少。同时，SOST基因抑制COL 1、OCN和OPN的表达，降低碱性磷酸酶活性，增加LPL和PPARγ的表达。此外，IL-17促进SOST基因诱导的脂肪生成，并增加对骨生成的抑制。结论：SOST促进了Th 17细胞的分化，降低了Treg细胞的分化，加剧了SOST基因对ADSCs成骨的抑制作用。
Background/Aims: Postmenopausal osteoporosis is considered to be an autoimmune and inflammatory process, and IL-17 plays important roles in the loss of bone mass. Sclerostin (SOST) acts as a negative regulator of bone formation by inhibiting the Wnt signaling pathway. It also is a mediator of the crosstalk between the skeletal and immune systems. However, few studies have examined the role of SOST gene in the differentiation of T helper 17 (Th17) cells. Methods: Adipose-derived stem cells (ADSCs) were isolated and transfected with pcDNA3-SOST or shSOST, and then co-cultured with CD4+ T cells isolated from peripheral blood mononuclear cells. The differentiation, adipogenesis, and osteogenesis of Th17 and regulatory T (Treg) cells were examined by western blot, intracellular and intranuclear staining, ELISA, and real-time quantitative PCR in this co-culture model. Results: The SOST gene promoted the secretion of IL-6 and TGF-β in ADSCs. After co-culture of ADSCs with CD4+ T cells, the SOST gene increased the number of CD4+IL-17+ cells and the levels of IL-17 and RORγ. However, the number of CD4+CD25+Foxp3+ cells was decreased, which was accompanied with a reduction of IL-10 and Foxp3 expression. In the meantime, the SOST gene inhibited the expression of COL1, OCN, and OPN, reduced the activity of alkaline phosphatase, and increased the expression of LPL and PPARγ. Furthermore, IL-17 promoted SOST gene-induced adipogenesis and increased the inhibition of osteogenesis. Conclusions: SOST promoted the differentiation of Th17 cells and reduced the differentiation of Treg cells, which exacerbated the SOST gene-induced inhibition of osteogenesis from ADSCs.