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bioRxiv · 10.1101/2025.09.15.676417

A Novel Proteoglycan-4 Isoform Drives Skeletal Regeneration

Tantawy, M.·Khajuria, D.·Norbury, C. C.·Kamal, F.·Elbarbary, R. A.
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Abstract

Proteoglycan 4 (PRG4) is an extracellular matrix protein best known for its lubricating role in articular cartilage. Using a murine model of tibial fracture, we performed RNA-seq across multiple post-fracture timepoints and observed high Prg4 expression during the first week of healing, coinciding with the initial inflammatory phase. Single-cell RNA-seq of the fracture callus localized Prg4 expression to a stem cell population with key roles in repair. Analysis of alternative splicing in callus RNA identified a unique Prg4 isoform lacking three coding exons (hereafter termed Prg4-S). In vivo knockdown of Prg4-S using locally delivered siRNA produced multiple defects that culminated in impaired bone formation. Together, these findings uncover an unanticipated osteogenic role for a unique Prg4 splicing isoform and highlight its potential for translational applications.

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Tantawy, M., Khajuria, D., Norbury, C. C., Kamal, F., Elbarbary, R. A.. 2025-09-18. A Novel Proteoglycan-4 Isoform Drives Skeletal Regeneration. https://doi.org/10.1101/2025.09.15.676417

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