蛋白磷酸酶SCP4通过葡萄糖代谢调节颞下颌关节软骨发育

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-05-23 DOI:10.1016/j.lfs.2025.123741

Jinjin Ma , Pinger Wang , Kaiao Zou , Zhen Zou , Linyi Zhou , Guangjun Liu , Xinyu Wang , Xinhua Feng , Xia Lin , Jianying Feng , Hongting Jin

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引用次数: 0

摘要

尽管越来越多的证据支持小羧基末端结构域（CTD）磷酸酶4 （SCP4）在代谢途径中的调节作用，但关于其在颞下颌关节（TMJ）软骨生长、发育和稳态维持中的作用及其分子基础的知识有限。因此，本研究旨在探讨SCP4在髁软骨软骨形成中的作用。方法制备软骨细胞特异性SCP4条件敲除小鼠（SCP4Col2Cre）。采用全骨染色、ABH/OG或HE染色、免疫组化等方法比较SCP4Col2Cre和cree阴性小鼠在产前和产后的软骨细胞分化和软骨发育。采用Micro-CT评估SCP4对小鼠软骨下骨的影响。并通过KEGG和GO富集分析评价相关生物学功能，进一步证实免疫组织化学染色、Western Blot、RT-PCR和海马实验。结果软骨细胞中SCP4缺失导致髁突软骨形成缺陷和基质生成受损。因此，SCP4Col2Cre小鼠骨体积分数（BV/TV）和骨小梁厚度（Tb.Th）显著降低，骨小梁分离（Tb.Sp）增加。此外，RNA-seq分析显示SCP4缺乏对葡萄糖代谢的影响。随后，我们在体内和体外证实了SCP4的缺失导致葡萄糖转运蛋白1 （Glut1）和其他葡萄糖代谢相关基因表达在产前和产后发育过程中的异常调控。我们在体外进一步证明，SCP4的缺失导致ATP的产生和细胞外酸化速率（ECAR）水平的增加，同时降低氧气消耗速率（OCR）水平。结论本研究强调SCP4在调节产前和产后TMJ软骨发育中的重要作用，部分通过异常上调glut1介导的葡萄糖代谢。

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Protein phosphatase SCP4 regulates temporomandibular joint cartilage development via glucose metabolism

Objective

Despite the growing evidence supporting the regulatory role of small carboxy-terminal domain (CTD) phosphatase 4 (SCP4) in metabolic pathways, limited knowledge exists concerning its involvement and molecular basis in temporomandibular joint (TMJ) cartilage growth, development, and homeostasis maintenance. Therefore, this study aims to investigate the role of SCP4 in chondrogenesis in condylar cartilage.

Methods

We generated chondrocyte-specific SCP4 conditional knockout mice (SCP4^Col2Cre). Whole skeletal staining, ABH/OG or HE staining, and immunohistochemistry were employed to compare chondrocyte differentiation and cartilage development between SCP4^Col2Cre and Cre-negative mice during prenatal and postnatal periods. The impact of SCP4 on subchondral bone in mice was assessed using Micro-CT. Additionally, relevant biological functions were evaluated by KEGG and GO enrichment analysis, which further confirmed immunohistochemical staining, Western Blot, RT-PCR and Seahorse experiment.

Results

Our findings demonstrated that the deficiency of SCP4 in chondrocytes resulted in defects in condylar chondrogenesis and impaired matrix production. Accordingly, the SCP4^Col2Cre mice exhibited a significant decrease in bone volume fraction (BV/TV) and trabecular thickness (Tb.Th), with an increase in trabecular separation (Tb.Sp). Furthermore, RNA-seq analysis showed the impact of SCP4 deficiency on glucose metabolism. Subsequently, we confirmed that the deficiency of SCP4 resulted in aberrant regulation of glucose transporter 1 (Glut1) and other glucose metabolism-related gene expression throughout prenatal and postnatal development in vivo and in vitro. We further demonstrated in vitro that the deletion of SCP4 led to increased ATP production and extracellular acidification rate (ECAR) levels, while concurrently reducing oxygen consumption rate (OCR) levels.

Conclusion

Our study emphasizes the crucial role of SCP4 in regulating prenatal and postnatal TMJ cartilage development, partly through aberrant upregulation of Glut1-mediated glucose metabolism.

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.