Stem Cells Dev. 2018 Jul 6. doi: 10.1089/scd.2018.0121. [Epub ahead of print]

Understanding tendons: lessons from transgenic mouse models.

Delgado Caceres M¹, Pfeifer C², Docheva D^3,4.

Abstract

Tendons and ligaments are connective tissues which have been comparatively less studied than muscle and cartilage/bone, even though they are crucial for proper function of the musculoskeletal system. In tendon biology, considerable progress has been made in identifying tendon-specific genes (Scleraxis, Mohawk, and Tenomodulin) in the past decade. However, besides tendon function and the knowledge of a small number of important players in tendon biology, neither the ontogeny of the tenogenic lineage nor signaling cascades have been fully understood. This resulting in major drawbacks in treatment and repair options following tendon degeneration. In this review, we have systematically evaluated publications describing tendon-related genes, which were studied in-depth and characterized by using knockout technologies and the subsequently generated transgenic mouse models (Tg) (knockout mice, KO). We report in a tabular manner, that from a total of 24 tendon-related genes, in 22 of the respective knockout mouse models, phenotypic changes were detected. Additionally, in some of the models it was described at which developmental stages these changes appeared and progressed. To summarize, only loss of Scleraxis and TGFbeta signaling led to severe tendon developmental phenotypes, whilst mice deficient for various proteoglycans, Mohawk, EGR1 and 2, and Tenomodulin presented mild phenotypes. This data suggests that the tendon developmental system is well organized, orchestrated, and backed up; this is even more evident amongst the members of the proteoglycan family, where the compensatory effects are much clearer. In future, it will be of great importance to discover additional master tendon transcription factors and the genes that play crucial roles in tendon development. This would improve our understanding of the genetic makeup of tendons, and to increase the chances to generate tendon specific drugs to advance overall treatment strategies.