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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.
Highlights
IntroductionMeniscus injuries are highly prevalent, affecting people of all ages and stages of life (Nielsen and Yde, 1991)
IL-1 treatment of inner zone cells resulted in significant downregulation (p < 0.05, log fold-change (LogFC) < −1) of 976 genes and upregulation (p < 0.05, LogFC > 1) of 1,129 genes (Figure 3A)
Dynamic tissue compression of meniscus tissue explants and dynamic tensile stretch of monolayer meniscus cells showed considerable concordance in RNA-sequencing results, the degree of overlap varied based on the anatomic region and presence of an inflammatory stimulus
Summary
Meniscus injuries are highly prevalent, affecting people of all ages and stages of life (Nielsen and Yde, 1991). Meniscus injury and subsequent surgery are linked to the development of post-traumatic osteoarthritis (PTOA), with 50% of partial meniscectomy patients developing radiographic osteoarthritis (OA) within 10–20 years following surgery (Lohmander et al, 2007). The avascular inner zone of the meniscus heals poorly due to the lack of blood supply (Rath and Richmond, 2000), repair of inner zone meniscal tears is still only recommended in limited cases (Gallacher et al, 2010; Ghazi Zadeh et al, 2018). The pathogenesis of PTOA following meniscus injury remains poorly understood, the involvement of inflammation-mediated tissue degradation is increasingly appreciated as a major contributing factor in disease progression. Even very low concentrations of IL-1 have been shown to cause degradation of meniscus tissue (McNulty et al, 2013) and inhibit repair in an explant model of meniscus injury (McNulty et al, 2007; Wilusz et al, 2008; McNulty et al, 2009)
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