tgif1缺乏通过pp2a介导的ERK1/2去磷酸化损害破骨细胞分化,并减轻小鼠骨质流失。

IF 5.9 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Miki Maeda, Hiroaki Saito, Amy B P Ribet, Eric Hesse, Hanna Taipaleenmäki
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引用次数: 0

摘要

骨重塑是一个受破骨细胞和成骨细胞活动调控的动态过程。这一过程中的不平衡会导致骨质疏松症,这是一种以低骨量和骨折风险增加为特征的疾病。同源结构域蛋白tg相互作用因子1 (Tgif1)先前已被确定为成骨细胞功能的关键调节因子。在这里,我们研究了Tgif1在破骨细胞中的细胞自主作用。我们的研究结果表明,Tgif1在破骨细胞前体中表达,在RANKL和m - csf诱导的分化过程中表达增加。在破骨细胞谱系中,Tgif1的缺失会损害破骨细胞的分化和吸收能力,从而减少小鼠体内与衰老相关的骨质流失。从机制上讲,Tgif1通过抑制ERK1/2磷酸酶蛋白磷酸酶2A (PP2A)来限制ERK1/2去磷酸化。抑制PP2A可恢复tgif1缺陷破骨细胞的分化受损,证实其参与了这一过程。这些发现证实Tgif1是破骨细胞分化、功能和骨吸收的重要调节因子,为研究控制骨量维持的分子机制提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Tgif1-deficiency impairs osteoclast differentiation through PP2A-mediated ERK1/2 dephosphorylation and attenuates bone loss in mice.

Bone remodeling is a dynamic process regulated by the activities of osteoclasts and osteoblasts. Imbalances in this process can lead to osteoporosis, a condition characterized by low bone mass and increased fracture risk. The homeodomain protein TG-interacting factor 1 (Tgif1) has been previously identified as a key regulator of osteoblast function. Here, we investigate the cell-autonomous role of Tgif1 in osteoclasts. Our findings reveal that Tgif1 is expressed in osteoclast precursors, with its expression increasing during RANKL and M-CSF-induced differentiation. Deletion of Tgif1 in the osteoclast lineage impairs osteoclast differentiation and resorption capacity, reducing aging-related bone loss in mice in vivo. Mechanistically, Tgif1 restricts ERK1/2 dephosphorylation by suppressing protein phosphatase 2A (PP2A), an ERK1/2 phosphatase. Inhibition of PP2A restores impaired differentiation of Tgif1-deficient osteoclasts, confirming its involvement in this process. These findings establish Tgif1 as an important regulator of osteoclast differentiation, function, and bone resorption, offering new insights into molecular mechanisms controlling bone mass maintenance.

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来源期刊
Journal of Bone and Mineral Research
Journal of Bone and Mineral Research 医学-内分泌学与代谢
CiteScore
11.30
自引率
6.50%
发文量
257
审稿时长
2 months
期刊介绍: The Journal of Bone and Mineral Research (JBMR) publishes highly impactful original manuscripts, reviews, and special articles on basic, translational and clinical investigations relevant to the musculoskeletal system and mineral metabolism. Specifically, the journal is interested in original research on the biology and physiology of skeletal tissues, interdisciplinary research spanning the musculoskeletal and other systems, including but not limited to immunology, hematology, energy metabolism, cancer biology, and neurology, and systems biology topics using large scale “-omics” approaches. The journal welcomes clinical research on the pathophysiology, treatment and prevention of osteoporosis and fractures, as well as sarcopenia, disorders of bone and mineral metabolism, and rare or genetically determined bone diseases.
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