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

  • Sci Adv. 2025 Jan 10;11(2):eadq4991. doi: 10.1126/sciadv.adq4991.
Chao Song  1  2 ,  Jasmin Koehnken Sawall  1 ,  Xing Ji  1 ,  Fangfang Song  1 ,  Xueyang Liao  1 ,  Renpeng Peng  2 ,  Hao Ren  2 ,  Eiki Koyama  1  3 ,  Maurizio Pacifici  1  3 ,  Fanxin Long  1  3
Affiliations
  • 1. Translational Research Program in Pediatric Orthopedics, Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 2. Department of Orthopedic Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
  • 3. Deaprtment of Orthopedic Surgery, University of Pennsylvania, Philadelphia, PA, USA.
PMID: 39772668 DOI: 10.1126/sciadv.adq4991
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 GLUT1 and/or GLUT3, in either the incipient pre-skeletal mesenchyme with Prx1Cre or in chondrocytes with Col2Cre, disrupted interzone formation dose-dependently. In contrast, deletion of GLUT1/3 in established interzone cells with Gdf5Cre did not have similar severe disruption of joint development. scRNA-seq revealed that GLUT1/3 deletion by Prx1Cre impeded Tgfβ signaling in the developing interzone cells. Direct elimination of Tgfβ signaling with Prx1Cre partially phenocopied the deletion of GLUT1/3 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.

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