ABSTRACT
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.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Arthritis, Experimental/immunology , Arthritis, Rheumatoid/immunology , MAP Kinase Kinase 4/metabolism , Nerve Tissue Proteins/metabolism , Osteoclasts/physiology , Adaptor Proteins, Signal Transducing/genetics , Animals , Disease Models, Animal , Disease Progression , Humans , Inflammation , Macrophage Activation , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , NF-kappa B/metabolism , Nerve Tissue Proteins/genetics , RAW 264.7 CellsABSTRACT
The aim of this study was to evaluate the clinical effect of core decompression (CD), lesion clearance, and bone graft in combination with Tongluo Shenggu decoction for the treatment of osteonecrosis of the femoral head (ONFH).A total of 75 patients (92 hips), with ONFH at Association Research Circulation Osseous (ARCO) stages II to IIIA, were studied and divided into treatment group and control group. In control group, patients were treated with the CD in combination with autologous or artificial ceramic bone graft. In treatment group, patients were treated with the above method combined with Tongluo Shenggu decoction. Patients were followed-up at 1 month, 6 months, and 24 months after surgery. The visual analogue scale (VAS) scores, Harris Hip Score (HSS), and total effective rates were measured and recorded.The total effective rate of the treatment group was significantly higher than that of the control group (97.2% vs. 89.9%, Pâ<â.05). Compared with preoperative, the VAS and HSS scores were both improved at final follow-up, and there was significant difference between 2 groups (Pâ<â.01).The combination of CD, lesion clearance, and the bone graft with Tongluo Shenggu decoction is safe and effective for the treatment of ONFH, owing to which it can provide higher postoperative functional outcomes, reduce pain, and achieve smaller osteonecrosis area and better bone changes.
