A Tale of Two Loads: Modulation of IL-1 Induced Inflammatory Responses of Meniscal Cells in Two Models of Dynamic Physiologic Loading

Abstract

Meniscus injuries are highly prevalent, and both meniscus injury and subsequent surgery are linked to the development of post-traumatic osteoarthritis (PTOA). Although the pathogenesis of PTOA remains poorly understood, the inflammatory cytokine IL-1 is elevated in synovial fluid following acute knee injuries and causes degradation of meniscus tissue and inhibits meniscus repair. Dynamic mechanical compression of meniscus tissue improves integrative meniscus repair in the presence of IL-1 and dynamic tensile strain modulates the response of meniscus cells to IL-1. Despite the promising observed effects of physiologic mechanical loading on suppressing inflammatory responses of meniscus cells, there is a lack of knowledge on the global effects of loading on meniscus transcriptomic profiles. In this study, we compared two established models of physiologic mechanical stimulation, dynamic compression of tissue explants and cyclic tensile stretch of isolated meniscus cells, to identify conserved responses to mechanical loading. RNA sequencing was performed on loaded and unloaded meniscus tissue or isolated cells from inner and outer zones, with and without IL-1. Overall, results from both models showed significant modulation of inflammation-related pathways with mechanical stimulation. Anti-inflammatory effects of loading were well-conserved between the tissue compression and cell stretch models for inner zone; however, the cell stretch model resulted in a larger number of differentially regulated genes. Our findings on the global transcriptomic profiles of two models of mechanical stimulation lay the groundwork for future mechanistic studies of meniscus mechanotransduction, which may lead to the discovery of novel therapeutic targets for the treatment of meniscus injuries.

A human meniscus explant model for studying early events in osteoarthritis development by proteomics

“…Cytokine treatment on nonhuman cartilage explants have been demonstrated to have an effect of increased release of ECM‐proteins and proteins involved in catabolic response of cartilage degradation into the explant culture media when compared to controls 48 . Combined mechanical loading and cytokine treatment on porcine and bovine meniscus was recently reported by McNulty et al in which two mechanical treatments were used; cell stretching and dynamic loading, using transcriptomics 49 . The inflammatory response was highly modulated by mechanical loading.…”

“…48 Combined mechanical loading and cytokine treatment on porcine and bovine meniscus was recently reported by McNulty et al in which two mechanical treatments were used; cell stretching and dynamic loading, using transcriptomics. 49 The inflammatory response was highly modulated by mechanical loading. In our study of menisci, we find release of ECM-and catabolic proteins, although the specific proteins released are to a large degree different than previous studies using a cartilage model.…”

Meniscus Repair: From In Vitro Research to Patients

“…IL-1 participates in the onset of OA as it leads to the expression of nitric oxide, matrix metalloproteinases that degrade the ECM of the meniscus tissue, and inhibits the proper mechanical properties as well as the repair of the fibrocartilage [113]. Interestingly, a recent study performed on meniscal explants of the inner and outer regions as well as isolated meniscus cells submitted to physiological mechanical loading (compression and cyclic tensile stretch), revealed that mechanical stimulation can strongly modulate the transcriptomic profile that is activated by IL-1, and can decrease the expression of genes involved in inflammatory signaling and OA development [114]. These new results open the hope of increasing the capacity of the meniscus for repair by targeting the meniscus mechanotransduction.…”