Wang Xinru, Dong Wei, Wang Xinyi, Wang Jiawei
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
Cell Signal. 2025 Mar;127:111617. doi: 10.1016/j.cellsig.2025.111617. Epub 2025 Jan 23.
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.
骨折是常见且严重的骨骼损伤，在加速骨折愈合的同时减轻患者痛苦仍是一项临床挑战。膜联蛋白A2（ANXA2）是一种广泛分布的、钙依赖性的、磷脂结合蛋白，参与骨重塑过程。然而，其在软骨细胞分化和软骨内成骨中的作用仍不清楚。在本研究中，我们发现ANXA2在生长板发育和骨折愈合过程中的软骨细胞中表达，在体外软骨细胞分化和成熟过程中也有表达，其最高表达出现在最活跃的分化阶段。此外，敲低ANXA2可抑制软骨细胞分化，而其过表达则显著促进软骨细胞分化。我们还证明，ANXA2通过介导STAT3的磷酸化和核转位以及激活PI3K/AKT途径来调节软骨形成和肥大分化。最后，将重组ANXA2蛋白注射到小鼠胫骨骨折部位，证实了其在促进骨折愈合过程中软骨内成骨的作用。总之，我们的研究表明，ANXA2部分通过STAT3和PI3K/AKT途径促进软骨细胞分化。这些发现为开发促进骨折愈合的新疗法提供了思路。
