Carbon nanotubes stimulate synovial inflammation by inducing systemic pro-inflammatory cytokines

Carbon nanotubes (CNTs) have promising applications in a wide range of biomedical fields, including imaging, drug/gene delivery and other therapeutics; however, the biosafety concerns of CNTs should be addressed. To date, many reports have documented the toxicological effects on the cells, tissue or organs that are in direct contact with the tubes; however, there is limited evidence to unravel the secondary toxicity upon CNT treatment. Moreover, more effort is needed to gain a definitive understanding of the adverse outcome pathway (AOP) for CNTs, and a pragmatic framework for risk assessment has not been established yet. In the current study, we aimed to decipher the secondary toxicity to joints under CNT exposure. We demonstrated that carboxylated multi-wall CNTs (MWCNTs-COOH) significantly provoked systemic pro-inflammatory responses, leading to synovial inflammation within knee joints, as evidenced by the infiltration of pro-inflammatory cells in the synovium and meniscus. Mechanistic studies showed that MWCNTs-COOH stimulated pro-inflammatory effects by activating macrophages, and the secreted pro-inflammatory cytokines primed the synoviocytes and chondrocytes, resulting in enhanced production of a large array of enzymes involved in articular cartilage degeneration, including matrix metalloproteinase (MMP) members and cyclooxygenase (COX) members, and increased enzymatic activity of MMPs was demonstrated. Blockade of the cytokines by antibodies significantly attenuated the production of these enzymes. Our current study thus suggests that there is a novel secondary toxicity of CNTs, namely a new AOP to understand the indirect effects of carbon nanotubes: synovial inflammation due to the alteration of the priming state of synoviocytes and chondrocytes under CNT-induced systemic inflammatory conditions.