Osteoarthritis (OA) is characterized by degradation of chondrocyte extracellular matrix (ECM). Accumulating evidence suggests that microRNAs (miRNAs) are associated with OA, but little is known of their function in chondrocyte ECM degradation. The objective of this study was to investigate the expression and function of miRNAs in OA. miRNA expression profile was determined in OA cartilage tissues and controls, employing Solexa sequencing and reverse transcription quantitative PCR (RT-qPCR). According to a modified Mankin scale, cartilage degradation was evaluated. Functional analysis of the miRNAs on chondrocyte ECM degradation was performed after miRNA transfection and IL-1β treatment. Luciferase reporter assays and western blotting were employed to determine miRNA targets. Expression of miR-221-3p was downregulated in OA cartilage tissues, which was significantly correlated with a modified Mankin scale. Through gain-of-function and loss-of-function studies, miR-221-3p was shown to significantly affect matrix synthesis gene expression and chondrocyte proliferation and apoptosis. Using SW1353 and C28I2 cells, SDF1 was identified as a target of miR-221-3p. SDF1 overexpression resulted in increased expression of catabolic genes such as MMP-13 and ADAMTS-5 in response to IL-1β, but these effects were moderated by miR-221-3p. SDF1 treatment antagonized this effect, while knockdown of SDF1 by shSDF1 induced inhibitory effects on the expression of CXCR4 and its main target genes, similar to miR-221-3p. The results indicate that upregulation of miR-221-3p could prevent IL-1β-induced ECM degradation in chondrocytes. Targeting the SDF1/CXCR4 signaling pathway may be used as a therapeutic approach for OA. miR-221-3p is downregulated in human cartilage tissues. miR-221-3p levels are associated with cartilage degeneration grade. miR-221-3p upregulation prevents IL-1β-induced ECM degradation in chondrocytes. Protection of ECM degradation by miR-223-3p occurs via SDF1/CXCR4 signaling. miR-221-3p is identified as a novel potential therapeutic target for osteoarthritis. KEY MESSAGES: miR-221-3p is downregulated in human cartilage tissues. miR-221-3p levels are associated with cartilage degeneration grade. miR-221-3p upregulation prevents IL-1β-induced ECM degradation in chondrocytes. Protection of ECM degradation by miR-223-3p occurs via SDF1/CXCR4 signaling. miR-221-3p is identified as a novel potential therapeutic target for osteoarthritis.
Osteogenic glue that reproduces the natural bone composition represents the final frontier of orthopedic adhesives with the potential to revolutionize surgical strategies against comminuted fractures. However, it is difficult to achieve an all-in-one formula, which could provide flexible and reliable adhesiveness while avoiding interfering with or even promoting the healing of glued fractures. Herein, an osteogenic glue characterized by inorganic-in-organic integration between amine-modified mesoporous bioactive glass nanoparticles (AMBGN) and bioadhesive gelatin-dextran network (GelDex) is introduced as an all-in-one tool to flexibly adhere and splice bone fragments and subsequently guide fracture healing during degradation. Relying on such integration, a 4-fold improvement in cohesiveness is presented, followed by a nearly 5-fold enhancement in adhesive strength in ex vivo porcine bone samples. The reversible and re-adjustable adhesiveness also enables glue to effectively splice intricate fragments from highly comminuted fractures in the rabbit radius in an in vivo environment. Moreover, well-preserved organic-inorganic integrity during degradation of the glue guides sustained interfacial osteogenesis and achieve satisfying healing outcomes in glued fractures, as observed by the 2-fold improvement in biomechanical and radiological performance compared with commercially available cyanoacrylate adhesives. The current findings propose an all-in-one solution for the fixation of bone fragments during surgery.
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