Mechanistic Insights into Cartilage Protection and Extracellular Matrix Remodeling: Transcriptome Analysis of Diclofenac Etalhyaluronate-treated Joint Tissues in Collagen-induced Arthritis Rats and Cytokine-stimulated Human Chondrocytes. Mammalia

Diclofenac etalhyaluronate (DF-HA, SI-613 ONO-5704) is a conjugate of hyaluronic acid and diclofenac, widely used for osteoarthritis treatment via intra-articular injection. To uncover unique mechanisms of DF-HA's cartilage protection, RNA sequencing was conducted on knee joint cartilage from arthritis rats and cytokine-stimulated chondrocytes. Genes specifically influenced by DF-HA were identified and analyzed. In arthritis rats, DF-HA suppressed extracellular matrix (ECM) remodeling and promoted the PTHR1 pathway, crucial for bone and cartilage development. Similarly, in cytokine-stimulated chondrocytes, DF-HA inhibited ECM remodeling, with changes in IGFBP4, MMP10, MMP13, and TIMP1 mirroring in vivo findings. These results highlight DF-HA's protective role in cartilage by targeting ECM remodeling pathways.

双氯芬酸透明质酸酯（Diclofenac etalhyaluronate，DF-HA，SI-613 ONO-5704）是透明质酸与双氯芬酸的共轭复合物，通过关节腔内注射广泛用于骨关节炎的治疗。为阐明DF-HA发挥软骨保护作用的独特机制，本研究对关节炎模型大鼠的膝关节软骨以及经细胞因子刺激的软骨细胞开展了RNA测序。研究鉴定并分析了受DF-HA特异性调控的基因。在关节炎模型大鼠中，DF-HA可抑制细胞外基质（extracellular matrix，ECM）重塑，并激活对骨骼与软骨发育至关重要的甲状旁腺激素1受体通路（PTHR1 pathway）。与之类似，在经细胞因子刺激的软骨细胞中，DF-HA也抑制了细胞外基质重塑，其引发的IGFBP4、MMP10、MMP13及TIMP1表达变化与体内实验结果一致。上述结果表明，DF-HA可通过靶向调控细胞外基质重塑通路发挥软骨保护作用。