c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 is a critical regulator for arthritis progression by meditating inflammation in mice model.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. However, the pathogenesis of RA is not fully understood. Here, we reported that c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1, also known as JNK-interacting protein 3 (JIP3)) was significantly important for collagen-induced arthritis (CIA) in mice. Mice with JIP3 knockout (JIP3) showed a significant decrease in arthritis index and swollen joint count in CIA mice. The histopathology of spleen and joint was markedly alleviated by JIP3 deficiency in CIA mice. Excessive macrophage activation in CIA mice was also inhibited by JIP3 deletion. CIA-induced RANKL/RANK/OPG system mRNA expression was blocked in JIP3-knockout mice. In addition, CIA-triggered cytokine secretion and TLRs/NF-κB activation was inactivated by JIP3-deficiency. In line with the inhibition of inflammation by JIP3-knockout, it also significantly suppressed JNK pathway activation induced by CIA, as evidenced by the down-regulation of p-JNK, p-c-Jun, AFT-2 and Elk-1 in joints. In vitro, RANKL-exposed RAW264.7 cells showed a significant reduction of osteoclast formation using TRAP staining. Moreover, JIP3 inhibition reduced the RANKL-caused expression of osteoclastic genes and inflammatory regulators, as well as activation of TLRs/NF-κB and JNK signaling pathways. Importantly, we found that promoting JNK activity could abrogate JIP3 knockdown-suppressed osteoclastic genes expression, inflammatory response and NF-κB activation. These findings suggested that JIP3 could significantly impede osteoclast formation and function by regulating JNK activation, illustrating a novel therapeutic strategy for managing arthritis and preventing bone destruction.