Species variations in tenocytes’ response to inflammation require careful selection of animal models for tendon research

Abstract

For research on tendon injury, many different animal models are utilized; however, the extent to which these species simulate the clinical condition and disease pathophysiology has not yet been critically evaluated. Considering the importance of inflammation in tendon disease, this study compared the cellular and molecular features of inflammation in tenocytes of humans and four common model species (mouse, rat, sheep, and horse). While mouse and rat tenocytes most closely equalled human tenocytes’ low proliferation capacity and the negligible effect of inflammation on proliferation, the wound closure speed of humans was best approximated by rats and horses. The overall gene expression of human tenocytes was most similar to mice under healthy, to horses under transient and to sheep under constant inflammatory conditions. Humans were best matched by mice and horses in their tendon marker and collagen expression, by horses in extracellular matrix remodelling genes, and by rats in inflammatory mediators. As no single animal model perfectly replicates the clinical condition and sufficiently emulates human tenocytes, fit-for-purpose selection of the model species for each specific research question and combination of data from multiple species will be essential to optimize translational predictive validity.

Mesenchymal Stem Cell-Derived Extracellular Vesicles in Tendon and Ligament Repair—A Systematic Review of In Vivo Studies

“…Horses had the shortest Mahalanobis distance to humans in terms of matrix remodelling proteinases, suggesting that horses are most suitable for assessing ECM production and tendon healing. However, rat tenocytes best resembled humans in terms of inflammatory mediators; furthermore, under healthy conditions, rat tenocytes had the shortest Mahalanobis distance with regards to overall gene expression [126], bringing into question Hurtig et al's proposition that large animals have more similar properties to humans.…”

“…It is accepted that no one animal model of tendon or ligament injury can perfectly replicate human pathology. Oreff et al calculated the Mahalanobis distances, a nondimensional measure of dissimilarity, of four model species to humans: mouse, rat, horse, and sheep, and found that the species that best matched humans depended on which functional group of genes were analysed [126]. Horses had the shortest Mahalanobis distance to humans in terms of matrix remodelling proteinases, suggesting that horses are most suitable for assessing ECM production and tendon healing.…”

Galvanic current activates the NLRP3 inflammasome to promote Type I collagen production in tendon

“…In all tendons, applying galvanic current application was found to have a similar clinical benefit, but we cannot rule out the fact that the calcaneal tendon of mice would present a different response to galvanic current. In fact, different species have been reported to have different inflammatory tenocyte responses (Oreff et al, 2021), and although mice and humans present high overall similarities in their tenocyte responses (Oreff et al, 2021), it is necessary to apply galvanic current in the presence of specific NLRP3 blockers, such as MCC950, in additional animal models with species other than mice.…”

Dynamic Load Model Systems of Tendon Inflammation and Mechanobiology

“…More specifically, combinatory effects of loading and culture conditions on inflammatory responses needs to be explored. Determining inflammatory effects in vitro is also further complicated by tenocyte response variations associated with the model species used (Oreff et al, 2021), which indicates the importance of selecting a model that most appropriately matches the research question.…”