Mesenchymal progenitor–derived proteoglycan 4 regulates the transdifferentiation of chondrocytes into osteoblasts during fracture healing

Abstract Introduction Proteoglycan 4 (PRG4), also known as lubricin, is essential for maintaining tissue homeostasis and acts as a lubricant that protects joint surfaces from wear and tear. Our previous studies have demonstrated that PRG4 plays multiple roles in wound healing in mice and pigs. Specifically, PRG4 derived from Hic1+ mesenchymal progenitor cells (MPCs) is crucial for maintaining tissue homeostasis in the dura mater near the spinal cord, and in the skin it contributes to ear wound healing in mice. Additionally, mice lacking PRG4 exhibit abnormal bone structure and function. However, the role of PRG4 in fracture healing remains unclear. Methods To investigate the role of PRG4 in fracture repair, we generated mice with a conditional deletion of Prg4 in the Hic1+ lineage. The presence and contribution of Hic1+ progenitors at the fracture site were assessed at 2‑ and 4‑weeks post‑injury (wpi). Bone healing quality was evaluated, and the cellular phenotype within the fracture callus was examined. Results We observed Hic1+ progenitors at the fracture site at both 2‑ and 4‑wpi. Conditional deletion of Prg4 in these progenitors impaired the quality of new bone formation at the fracture site. Furthermore, PRG4 was required to maintain the cartilaginous phenotype of callus cells. In its absence, chondrocytes underwent premature transformation into osteoblasts, disrupting the normal progression of fracture healing. Discussion These findings provide new insights into the role of PRG4 in bone regeneration. PRG4, derived from Hic1+ MPCs, is critical for regulating the balance between chondrogenesis and osteogenesis during fracture repair. By preventing premature chondrocyte‑to‑osteoblast transition, PRG4 supports proper callus formation and bone healing. This work highlights the importance of PRG4 and Hic1+ MPCs in fracture repair and extends their known functions in tissue homeostasis and wound healing.