ANXA2 promotes chondrocyte differentiation and fracture healing by regulating the phosphorylation of STAT3 and PI3K/AKT signaling pathways

Fractures are common and serious skeletal injuries, and accelerating their healing while alleviating patient suffering remains a clinical challenge. Annexin A2 (AnxA2) is a widely distributed, calcium-dependent, phospholipid-binding protein involved in bone remodeling. However, its role in chondrocyte differentiation and endochondral ossification remains unclear. In this study, we found that AnxA2 is expressed in chondrocytes during growth plate development and fracture healing, as well as during chondrocyte differentiation and maturation in vitro, with its highest expression occurring in the most active differentiation phase. Moreover, AnxA2 knockdown inhibited chondrocyte differentiation, while its overexpression significantly promoted it. We also demonstrated that AnxA2 regulates the chondrogenic and hypertrophic differentiation by mediating the phosphorylation and nuclear translocation of STAT3, as well as activating the PI3K/Akt pathway. Finally, recombinant AnxA2 protein was injected into the tibial fracture sites of mice, verifying its role in promoting endochondral ossification during fracture healing. In conclusion, our study shows that AnxA2 promotes chondrocyte differentiation, partially through the STAT3 and PI3K/Akt pathways. These findings provide insights that could aid in developing new therapies to enhance fracture healing.

ANXA2; Chondrocyte; Endochondral ossification; Fracture; STAT3.