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

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.