Search

Mechanical factors play a critical role in the physiology and pathology of articular cartilage, although the mechanisms of mechanical signal transduction are not fully understood. We undertook this study to test the hypothesis that type VI collagen is necessary for mechanotransduction in articular cartilage by determining the effects of type VI collagen knockout on the activation of the mechano-osmosensitive, calcium-permeable channel TRPV4 (transient receptor potential vanilloid channel 4) as well as on osmotically induced chondrocyte swelling and pericellular matrix (PCM) mechanical properties.Confocal laser scanning microscopy was used to image TRPV4-mediated calcium signaling and osmotically induced cell swelling in intact femora from 2- and 9-month-old wild-type (WT) and type VI collagen-deficient (Col6a1(-/-)) mice. Immunofluorescence-guided atomic force microscopy was used to map PCM mechanical properties based on the presence of perlecan.Hypo-osmotic stress-induced TRPV4-mediated calcium signaling was increased in Col6a1(-/-) mice relative to WT controls at 2 months. Col6a1(-/-) mice exhibited significantly increased osmotically induced cell swelling and decreased PCM moduli relative to WT controls at both ages.In contrast to our original hypothesis, type VI collagen was not required for TRPV4-mediated Ca(2+) signaling; however, knockout of type VI collagen altered the mechanical properties of the PCM, which in turn increased the extent of cell swelling and osmotically induced TRPV4 signaling in an age-dependent manner. These findings emphasize the role of the PCM as a transducer of mechanical and physicochemical signals, and they suggest that alterations in PCM properties, as may occur with aging or osteoarthritis, can influence mechanotransduction via TRPV4 or other ion channels.

Background: Malignant melanoma is a highly aggressive cancer that spreads and metastasizes quickly. In recent years, the antiangiogenic drug bevacizumab has been trialed to treat malignant melanoma. We conducted the first meta-analysis to examine the efficacy and safety of bevacizumab combined with other drugs in malignant melanoma. Methods: We searched for randomized controlled trials (RCTs) and non-comparative clinical studies of bevacizumab combined with chemotherapy, targeted medicine, and interferon to treat malignant melanoma in PubMed, Embase, the Cochrane Library, and Web of Science. Meta-analysis of RCT was performed using Review Manager (version 5.4), and non-comparative meta-analysis was performed using R (version 4.0.3). The primary outcome was the objective response rate. Depending on the heterogeneity of the included studies, the pooled outcomes and 95% CI were calculated using either random-effects or fixed-effect models. Subgroup outcomes were calculated with possible relevant variables. Sensitivity analyses were carried out by excluding each study from the highly heterogeneous pooled results in turn. Funnel plot and Begg's test were used to test the included studies' potential publication bias. The level of significance was set at p < 0.05. Results: This meta-analysis included 20 trials: five RCTs and 15 non-comparative clinical studies with a total of 23 bevacizumab intervention arms. In 14 treatment arms, bevacizumab was combined with chemotherapy drugs such as fotemustine, dacarbazine, carboplatin/paclitaxel, and temozolomide. In six treatment arms, bevacizumab was combined with targeted medicines such as imatinib, everolimus, sorafenib, erlotinib, and temsirolimus. There were also six treatment arms that used bevacizumab in combination with interferon. The pooled objective response rate was 15.8% (95% CI, 11.4%-20.2%). Bevacizumab plus carboplatin/paclitaxel significantly increased the overall survival compared to carboplatin/paclitaxel (HR = 0.64, 95% CI, 0.49-0.85, p < 0.01). Fatigue, nausea, leukopenia, thrombocytopenia, and neutropenia were the most common adverse events. The pooled incidence of hypertension of all bevacizumab arms in malignant melanoma was 32.4% (95% CI, 24.5%-40.3%). Conclusion: This study showed that bevacizumab combined with chemotherapy might be effective and well-tolerated in patients with stage III or IV unresectable malignant melanoma. Systematic Review Registration : [https://www.crd.york.ac.uk/PROSPERO/display&#95;record.php?RecordID=304625], identifier [CRD42022304625]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Han, Ge, Liu, Yang, Zhang, Wang and Liang.)