Abstract
Tendons and ligaments are connective tissues that 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 results 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 TGFβ signaling led to severe tendon developmental phenotypes, while mice deficient for various proteoglycans, Mohawk, EGR1 and 2, and Tenomodulin presented mild phenotypes. These data suggest that the tendon developmental system is well organized, orchestrated, and backed up; this is even more evident among 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 will increase the chances of generating tendon-specific drugs to advance overall treatment strategies.
Highlights
Tendon development, critical factors and signaling cascadesThe establishment of a proper musculoskeletal system involves the finely orchestrated development of muscle, cartilage, and tendon lineages emerging from the somitic mesoderm [1]
The tendon lineage is formed within the dorsolateral sclerotome, adjacent to and beneath the myotome, in a somite subdomain denominated as syndetome [1]
The main disadvantage of a constitutive knockout system is the fact, that roughly onethird of the genes present in mammals (*8,000 genes in mice) are essential. This means that the deletion of two copies of some genes may either lead to embryonic or postnatal lethality, or could activate a nonregulated expression of other compensatory genes [62]
Summary
Tendons and ligaments are connective tissues that have been comparatively less studied than muscle and cartilage/ bone, even though they are crucial for proper function of the musculoskeletal system. Only loss of Scleraxis and TGFb signaling led to severe tendon developmental phenotypes, while mice deficient for various proteoglycans, Mohawk, EGR1 and 2, and Tenomodulin presented mild phenotypes. These data suggest that the tendon developmental system is well organized, orchestrated, and backed up; this is even more evident among the members of the proteoglycan family, where the compensatory effects are much clearer. 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 will increase the chances of generating tendon-specific drugs to advance overall treatment strategies
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