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转化生长因子β信号通路刺激糖酵解，以促进发育中小鼠胚胎肢体滑膜关节中间带的形成。

Tgfβ signaling stimulates glycolysis to promote the genesis of synovial joint interzone in developing mouse embryonic limbs.

作者信息

Song Chao, Sawall Jasmin Koehnken, Ji Xing, Song Fangfang, Liao Xueyang, Peng Renpeng, Ren Hao, Koyama Eiki, Pacifici Maurizio, Long Fanxin

机构信息

Translational Research Program in Pediatric Orthopedics, Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Department of Orthopedic Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.

出版信息

Sci Adv. 2025 Jan 10;11(2):eadq4991. doi: 10.1126/sciadv.adq4991. Epub 2025 Jan 8.

DOI:10.1126/sciadv.adq4991
PMID:39772668
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11708888/
Abstract

The initial interzone cells for synovial joints originate from chondrocytes, but such critical transition is minimally understood. With single-cell RNA sequencing (scRNA-seq) of murine embryonic knee joint primordia, we discovered that heightened expression of glycolysis genes characterized developing interzone cells when compared to flanking chondrocytes. Conditional deletion of the glucose transporters and/or , in either the incipient pre-skeletal mesenchyme with or in chondrocytes with , disrupted interzone formation dose-dependently. In contrast, deletion of / in established interzone cells with did not have similar severe disruption of joint development. scRNA-seq revealed that deletion by impeded Tgfβ signaling in the developing interzone cells. Direct elimination of Tgfβ signaling with partially phenocopied the deletion of in impairing interzone formation. Tgfβ stimulated glycolysis in chondrocytes via activation of mTOR and Hif1α in vitro. The data support that the essential conversion of chondrocytes to interzone cells requires a transient elevation of glycolysis partly dependent on Tgfβ signaling.

摘要

滑膜关节的初始中间区细胞起源于软骨细胞，但这种关键转变的了解极少。通过对小鼠胚胎膝关节原基进行单细胞RNA测序（scRNA-seq），我们发现与相邻软骨细胞相比，糖酵解基因的高表达是发育中的中间区细胞的特征。在带有Prx1的早期前骨骼间充质或带有Col2a1-Cre的软骨细胞中条件性缺失葡萄糖转运蛋白Glut1和/或Glut3，会剂量依赖性地破坏中间区形成。相比之下，在带有Col2a1-Cre的已建立中间区细胞中缺失Glut1/Glut3，对关节发育没有类似的严重破坏。scRNA-seq显示，Prx1介导的Glut1缺失阻碍了发育中的中间区细胞中的Tgfβ信号传导。用SB431542直接消除Tgfβ信号传导在损害中间区形成方面部分模拟了Glut1的缺失。Tgfβ在体外通过激活mTOR和Hif1α刺激软骨细胞中的糖酵解。数据支持软骨细胞向中间区细胞的必要转变需要糖酵解的短暂升高，部分依赖于Tgfβ信号传导。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f91/11708888/47be66d339a9/sciadv.adq4991-f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f91/11708888/16438b3b2455/sciadv.adq4991-f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f91/11708888/31f871087408/sciadv.adq4991-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f91/11708888/c7118943fa47/sciadv.adq4991-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f91/11708888/47be66d339a9/sciadv.adq4991-f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f91/11708888/16438b3b2455/sciadv.adq4991-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f91/11708888/379d68a2c0fa/sciadv.adq4991-f2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f91/11708888/b7a228a15497/sciadv.adq4991-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f91/11708888/d08e175385a8/sciadv.adq4991-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f91/11708888/6eb63ebb3d44/sciadv.adq4991-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f91/11708888/31f871087408/sciadv.adq4991-f8.jpg
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