Imrecoxib attenuates osteoarthritis by modulating synovial macrophage polarization through inactivating COX-2/PGE2 signaling pathway

Peng Peng^1*Wanling Zheng¹Jiawei Shen²Yuchen Liu¹Jingyuan Huang³Bin Zhang³Yanqun Qiu^1*Jiangang Cao^4*

• ¹Huashan Hospital, Fudan University, Shanghai, Shanghai Municipality, China
• ²Second Affiliated Hospital, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
• ³Tianjin Medical University General Hospital, Tianjin, China
• ⁴Tianjin Hospital, Tianjin, Tianjin, China

Introduction: Although biomaterials strategies have been regarded as a promising approach for the treatment of osteoarthritis (OA), identifying novel drugs to be delivered for modulate macrophage polarization is still unclear. As a commonly used non-steroidal anti-inflammatory drug for OA, Imrecoxib may be a novel drug to direct and sustain macrophage phenotype. However, the specific protective mechanism of Imrecoxib in OA remains unclear. This study aims to investigate whether Imrecoxib would treat OA by regulating synovial macrophage polarization. Methods: The research involves constructing mouse destabilization of medial meniscus (DMM) model to assess the changes in pain, bone destruction, cartilage degeneration, and synovial macrophage phenotypes following Imrecoxib treatment. Additionally, the effects of macrophage conditioned media (CM) pretreated with Imrecoxib on the chondrocyte apoptosis, inflammation and degeneration-related factor expression were evaluated. The role of COX-2/PGE2 signaling pathway in the macrophage phenotype changes was further investigated. Results: We found that Imrecoxib alleviated pain, cartilage degeneration and synovitis, promoted polarization of M1 macrophages toward M2 phenotype in vivo and in vitro. In vitro experiments, Imrecoxib-CM protected chondrocyte by modulating macrophage polarization. Furthermore, Imrecoxib regulates macrophage polarization through the COX-2/PGE2 pathway. Conclusions: This study unravels that Imrecoxib protects joint cartilage and attenuates osteoarthritis by modulating synovial macrophage polarization through inactivating COX-2/PGE2 signaling pathway, providing new drug delivery strategy for the clinical treatment of OA.