DLK1 and DLK2, two non-canonical ligands of NOTCH receptors, differentially modulate the osteogenic differentiation of mesenchymal C3H10T1/2 cells.

IF 4.3 2区 生物学 Q1 BIOLOGY Biological Research Pub Date : 2024-10-30 DOI:10.1186/s40659-024-00561-7
María-Milagros Rodríguez-Cano, María-Julia González-Gómez, Eva-María Monsalve, María-José M Díaz-Guerra, Moustapha Kassem, Jorge Laborda, María-Luisa Nueda, Victoriano Baladrón
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引用次数: 0

Abstract

Background: C3H10T1/2 is a mesenchymal cell line capable of differentiating into osteoblasts, adipocytes and chondrocytes. The differentiation of these cells into osteoblasts is modulated by various transcription factors, such as RUNX2. Additionally, several interconnected signaling pathways, including the NOTCH pathway, play a crucial role in modulating their differentiation into mature bone cells. We have investigated the roles of DLK1 and DLK2, two non-canonical inhibitory ligands of NOTCH receptors, in the osteogenic differentiation of C3H10T1/2 cells.

Results: Our results corroborate existing evidence that DLK1 acts as an inhibitor of osteogenesis. In contrast, we demonstrate for the first time that DLK2 enhances this differentiation process. Additionally, our data suggest that NOTCH2, 3 and 4 receptors may promote osteogenesis, as indicated by their increased expression during this process, whereas NOTCH1 expression, which decreases during cell differentiation, might inhibit osteogenesis. Moreover, treatment with DAPT, a NOTCH signaling inhibitor, impeded osteogenic differentiation. We have confirmed the increase in ERK1/2 MAPK and p38 MAPK phosphorylation in C3H10T1/2 cells induced to differentiate to osteoblasts. Our new findings reveal increased ERK1/2 MAPK phosphorylation in differentiated C3H10T1/2 cells with a decrease in DLK1 expression or an overexpression of DLK2, which is coincident with the behavior of those transfectants where we have detected an increase in osteogenic differentiation. Additionally, p38 MAPK phosphorylation increases in differentiated C3H10T1/2 cells with reduced DLK1 levels.

Conclusions: Our results suggest that DLK1 may inhibit osteogenesis, while DLK2 may promote it, by modulating NOTCH signaling and the phosphorylation of ERK1/2 and p38 MAPK pathways. Given the established inhibitory effect of DLK proteins on NOTCH signaling, these new insights could pave the way for developing future therapeutic strategies aimed at treating bone diseases.

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NOTCH受体的两种非经典配体DLK1和DLK2对间充质C3H10T1/2细胞的成骨分化具有不同的调节作用。
背景:C3H10T1/2 是一种间充质细胞系,能够分化成成骨细胞、脂肪细胞和软骨细胞。这些细胞向成骨细胞的分化受 RUNX2 等多种转录因子的调控。此外,包括 NOTCH 通路在内的几种相互关联的信号通路在调节它们向成熟骨细胞的分化过程中发挥着至关重要的作用。我们研究了DLK1和DLK2这两种NOTCH受体的非经典抑制配体在C3H10T1/2细胞成骨分化过程中的作用:结果:我们的研究结果证实了现有的证据,即 DLK1 是成骨的抑制剂。相反,我们首次证明了 DLK2 能促进这一分化过程。此外,我们的数据还表明,NOTCH2、3 和 4 受体在成骨过程中的表达增加可能会促进成骨,而在细胞分化过程中表达减少的 NOTCH1 可能会抑制成骨。此外,NOTCH 信号抑制剂 DAPT 会阻碍成骨分化。我们证实,在诱导分化成成骨细胞的 C3H10T1/2 细胞中,ERK1/2 MAPK 和 p38 MAPK 磷酸化增加。我们的新发现表明,在 DLK1 表达减少或 DLK2 表达过多的分化 C3H10T1/2 细胞中,ERK1/2 MAPK 磷酸化增加,这与我们检测到成骨分化增加的转染细胞的行为相吻合。此外,在DLK1水平降低的已分化的C3H10T1/2细胞中,p38 MAPK磷酸化增加:我们的研究结果表明,DLK1 可抑制成骨,而 DLK2 可通过调节 NOTCH 信号以及 ERK1/2 和 p38 MAPK 通路的磷酸化促进成骨。鉴于DLK蛋白对NOTCH信号转导的抑制作用已被证实,这些新发现可为开发未来治疗骨病的策略铺平道路。
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来源期刊
Biological Research
Biological Research 生物-生物学
CiteScore
10.10
自引率
0.00%
发文量
33
审稿时长
>12 weeks
期刊介绍: Biological Research is an open access, peer-reviewed journal that encompasses diverse fields of experimental biology, such as biochemistry, bioinformatics, biotechnology, cell biology, cancer, chemical biology, developmental biology, evolutionary biology, genetics, genomics, immunology, marine biology, microbiology, molecular biology, neuroscience, plant biology, physiology, stem cell research, structural biology and systems biology.
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