The activation of TNF-α/NF-кB signaling is involved in the regulation of a wide range of biological processes, such as cell proliferation, differentiation and apoptosis, eventually causing a number of diseases, such as cancer and inflammation. Here, we found that TNF-α/NF-кB signaling was activated in a large number of blood samples taken from foot and ankle rheumatoid arthritis (RA) patients. By applying a microarray assay to the human synovial sarcoma cell line SW982 and the human fibroblast-like synoviocyte cell line HFLS-RA, as well as in their corresponding p65 knockdown and -overexpressing cells, we identified and verified the activation of many p65 targets, including cytokines (e.g., TNF-α and IL-6), chemokines (e.g., MCP-1 and PANTES), protein receptors (e.g., CD-40 and MHC-1), and inducible enzymes (e.g., COX2). In addition, we subjected microRNAs from foot and ankle RA patients to a microRNA-specific microarray and found that miR-7-5p targeted the 3'-UTR of p65, negatively regulating its expression. By applying an in vitro screen to identify small molecules that specifically inhibited the interaction between TRADD and TNFR2, we found that NSM00191 strongly inhibited the activation of TNF-α/NF-кB signaling in vitro and in vivo, causing the downregulation of NF-кB targets and the decrease of arthritis scores. Collectively, our findings shed new light on the regulation of the TNF-α/NF-кB axis and might provide a new avenue for RA treatment.

This retrospective study aimed to introduce a novel method for simultaneous Y-shape osteotomy combined with subtalar arthrodesis for calcaneus malunion and to evaluate the feasibility of this method. We retrospectively analysed the clinical and imaging data of 11 patients with calcaneus malunion treated using Y-shape osteotomy and subtalar arthrodesis who were admitted to our hospital from June 2018 to October 2020. The patients included 9 males and 2 females aged from 24 to 69 years old, with an average age of 42.18 years. The clinical and radiological results were assessed with the Visual Analogue Scale (VAS) pain score and American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot score. In addition, functional recovery and general quality of life were evaluated using the 12-Item Short-Form Survey (SF-12). All radiological parameters were significantly improved at the last follow-up, with increases of 14.37°, 9.18°, and 4.51 mm in the Böhler’s angle, calcaneal pitch angle, and talocalcaneal height, respectively, and decreases of 6.39 mm and 6.18° in the calcaneal width and Hindfoot alignment angle (p < 0.05). The mean AOFAS and VAS scores at the last follow-up improved compared with those preoperatively, from 34.18 ± 9.53 to 84.18 ± 11.59 and from 6.90 ± 1.22 to 1.90 ± 1.13, respectively (p < 0.05). The SF-12 physical and mental health scores were 49.65 ± 6.84 and 52.68 ± 7.88, respectively. Furthermore, the early postoperative complications included skin necrosis in one and sural neuralgia in one patient, and the late postoperative complication included ankle pain in one patient. No other complications, such as implant discomforts, malunion, nonunion and re-fracture, were presented. These results indicate that Y-shape osteotomy combined with subtalar arthrodesis is an effective new method for the treatment of calcaneal malunion. Advantages include improvement of the anatomic shape of the calcaneus and union rates for subtalar arthrodesis.