# Targeting the PTN/PTPRZ1-ROS Pathway to Promote Bone Regeneration

## TL;DR

This study shows that PTN promotes bone regeneration by reducing cell death and ROS in bone marrow stem cells, offering a new treatment target for osteoporosis.

## Contribution

The study identifies PTN's mechanism of action via the PTPRZ1-ROS pathway in promoting osteogenesis and validates it in osteoporotic animals.

## Key findings

- PTN inhibits apoptosis and promotes osteogenic differentiation of rBMSCs.
- PTN reduces ROS levels and enhances antioxidant functions in rBMSCs.
- PTN binds to PTPRZ1, activating PLCG1 and NCOA3 to regulate osteogenesis.

## Abstract

Background: Osteoporosis is a global health problem that significantly decreases patients’ quality of life and causes tremendous medical burdens. Therefore, exploring effective targeting strategies for osteoporosis treatment is crucial. Previous studies have indicated that pleiotrophin (PTN) was a secretory factor involved in several biological processes, such as angiogenesis, neural development, and abnormal osteogenic functions in osteoporosis. However, the roles of PTN in osteogenics and the mechanisms remain unclear. Methods: In this study, we explored the effects and mechanisms of PTN in regulating osteogenic functions using real-time quantitative PCR, immunofluorescence, ALP detection, a TUNEL assay, RNA sequencing, and phosphorylation quantitative proteomics. Fracture-healing experiments in osteoporosis rats were also conducted to evaluate the osteogenic functions of PTN in vivo. Results: We found that PTN significantly inhibited apoptosis and promoted the osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs). Further experiments showed that PTN regulated the biological functions of rBMSCs by promoting antioxidant functions and reducing cellular reactive oxygen species (ROS), thereby protecting rBMSCs from accumulated ROS. Additionally, we found that PTN binds to the PTPRZ1 receptor, inducing intracellular PLCG1 phosphorylation and NCOA3 nuclear translocation, which regulate the downstream antioxidant functions of rBMSCs. Additionally, we verified that PTN effectively promoted fracture healing in osteoporotic animals. Conclusions: This study elucidates the mechanisms by which PTN promotes osteogenesis and verifies this effect in vivo, offering an effective target for osteoporosis treatment.