Zhengquan Huang

Macrophages and fibroblasts are the main effector cells in synovial tissue in the knee joint. Our previous studies showed that there was synovial macrophage pyroptosis in knee osteoarthritis (KOA) and that inhibiting this pyroptosis could alleviate synovial fibrosis. In the present study, we aimed to elucidate the mechanism by which macrophage pyroptosis affects synovial fibrosis. We established an LPS/ATP-induced model in macrophages that mimicked the inflammatory environment of KOA and induced macrophage pyroptosis. The TGF-β1, SMAD3, and P-SMAD3, and the synovial fibrosis markers (Collagen I, TIMP1, Vimentin, and TGF-β1) were significantly decreased after fibroblasts were cultured with RAGE inhibitors and SMAD3 inhibitors. Moreover, ELISA and immunofluorescence analysis showed that macrophage pyroptosis induced the release of IL-1β, IL-18, and HMGB1 and caused the translocation of HMGB1 from the fibroblast nucleus to the cell membrane, where it could bind with RAGE. Subsequently, in the synovial tissue of KOA model rats, we observed that inhibiting HMGB1, RAGE, and SMAD3 could alleviate the expression of synovial fibrosis markers (Collagen I, TIMP1, Vimentin, and TGF-β1) at both the mRNA and protein levels. Besides, HE and Sirius Red staining were used to observe the transverse diameter of the right knee. In conclusion, macrophage pyroptosis induced IL-1β, IL-18, and HMGB1, which could be caused HMGB1 to translocate from the fibroblast nucleus and bind with RAGE, activating the TGF-β1/SMAD3 signaling pathway and affecting synovial fibrosis.

Objective The aim of this meta-analysis was to clarify the role of Matrix metalloproteinase 1 (MMP-1) -1607 1G/2G (rs1799750) polymorphism on the osteoarthritis (OA) risk. Methods Articles were selected by retrieving the Web of Science, Embase and Pubmed. The strength of the association between -1607 1G/2G polymorphism and OA risk was assessed by odds ratios (ORs) with the corresponding 95% confidence interval (CI) for each study. Results No significant association between -1607 1G/2G polymorphism and OA risk was found in all the models overall (2G2G vs 1G1G, OR (95%CI) = 0.69 (0.36–1.32), P = 0.54; 2G2G + 2G1G vs 1G1G, OR (95%CI) = 0.88 (0.47–1.63), P = 0.69; 2G2G vs 2G1G + 1G1G, OR (95%CI) = 1.30 (0.68–2.47), P = 0.41; 2 G vs 1G, OR (95%CI) = 0.90 (0.86–1.54), P = 0.66). By subgroup analysis, significant association was found in the “< 60 years” group (2G2G vs 1G1G, OR (95%CI) = 3.46 (2.13–5.62), P = 0.00; 2G2G + 2G1G vs 1G1G, OR (95%CI) = 0.49 (0.31–0.79), P = 0.00; 2G2G vs 2G1G + 1G1G, OR (95%CI) = 2.74 (1.80–4.16, P = 0.00; 2 G vs 1G, OR (95%CI) = 0.56 (0.35–0.89), P = 0.01). Conclusions This meta-analysis showed that -1607 1G/2G polymorphism may increase the susceptibility to OA among the younger populations (<60 years). More studies with detailed information are needed to validate our conclusion. Level of Evidence Level I Diagnostic Study. ER -

Chondrocyte apoptosis is a central feature in the progression of osteoarthritis (OA), and would be triggered by sustained elevation of intracellular calcium ion (Ca2+), also known as a cellular second messenger. Transient receptor potential ankyrin 1 (TRPA1) is a membrane-associated cation channel, and the activation of which causes an influx of cation ions, in particularly Ca2+, into the activated cells. Therefore, we investigate the potential role of TRPA1 in mediating Ca2+ influx to promote chondrocyte apoptosis in OA. The expression of TRPA1 in interleukin (IL)-1β-treated rat chondrocytes was assessed by Polymerase chain reaction (PCR) and Western blot (WB), and the functionality of TRPA1 channel by Ca2+ influx measurements. Meanwhile, the chondrocyte apoptosis in IL-1β-treated cells was measured by TUNEL assay and flow cytometry. The measurement of mitochondrial membrane potential and apoptosis-associated proteins after inhibition of TRPA1 were also performed in IL-1β-treated rat chondrocytes. After being induced by IL-1β, the gene and protein expression of TRPA1 was increased in the dose-dependent manner. Meanwhile, Ca2+ influx mediated by TRPA1 in rat chondrocytes was also enhanced. Pharmacological inhibition of TRPA1 downregulated the apoptotic rate in IL-1β-treated rat chondrocytes. In addition, the membrane potential depolarization was improved and significantly increased expression of apoptosis-associated proteins also reduced by the TRPA1 antagonist. We found the IL-1β caused the increased functional expression of TRPA1, the activation of which involved IL-1β-induced apoptosis in rat chondrocytes. The potential mechanism may be linked to the intracellular calcium overload mediated by TRPA1 and attendant mitochondrial dysfunction.