Regeneration of Damaged Tendon-Bone Junctions (Entheses)—TAK1 as a Potential Node Factor

Abstract

Musculoskeletal dysfunctions are highly prevalent due to increasing life expectancy. Consequently, novel solutions to optimize treatment of patients are required. The current major research focus is to develop innovative concepts for single tissues. However, interest is also emerging to generate applications for tissue transitions where highly divergent properties need to work together, as in bone-cartilage or bone-tendon transitions. Finding medical solutions for dysfunctions of such tissue transitions presents an added challenge, both in research and in clinics. This review aims to provide an overview of the anatomical structure of healthy adult entheses and their development during embryogenesis. Subsequently, important scientific progress in restoration of damaged entheses is presented. With respect to enthesis dysfunction, the review further focuses on inflammation. Although molecular, cellular and tissue mechanisms during inflammation are well understood, tissue regeneration in context of inflammation still presents an unmet clinical need and goes along with unresolved biological questions. Furthermore, this review gives particular attention to the potential role of a signaling mediator protein, transforming growth factor beta-activated kinase-1 (TAK1), which is at the node of regenerative and inflammatory signaling and is one example for a less regarded aspect and potential important link between tissue regeneration and inflammation.

Effects of hindlimb unloading and subsequent reloading on the structure and mechanical properties of Achilles tendon‐to‐bone attachment

“…The Achilles tendon enthesis, which transmits the force from the soleus and gastrocnemius muscles to the calcaneus, is a fibrocartilaginous enthesis 13 . The molecules that compose the enthesis and their organization allow stress to be dissipated and protect the structure from the risk of failure during the transmission of forces 11,14 . As collagens and minerals mainly determine the tensile properties of the interface, 12,15–16 proteoglycans (PG) reflect the compressive forces to which the enthesis is subjected and are thought to protect the enthesis against shear, wear, and tear 12,17 …”

Dynamic Load Model Systems of Tendon Inflammation and Mechanobiology

“…Mechanical loading of tendon tissue is essential for tendon maturation during development, tendon homeostasis, and degeneration. Many reviews focus in-depth on the history of understanding matrix turnover, tendon biomechanics, and the methods/models used to understand tendon as well as ligament mechanobiology (Lavagnino et al, 2015;Thomopoulos et al, 2015;Wang and Chen, 2018;Dyment et al, 2020;Friese et al, 2020;Gracey et al, 2020;Wang et al, 2020;Bramson et al, 2021). In addition, in vivo models of tendon degeneration are the focus of another review (Theodossiou and Schiele, 2019).…”

Innovative Strategies in Tendon Tissue Engineering

“…On the other hand, the calcified fibrocartilage is an avascular and irregular zone, populated by fibrochondrocytes and consisting of type I, II and X collagen, which represents the true junction to the bone. It provides the mechanical integrity of the insertion, allowing the mechanical transition of force across the insertion [ 30 , 31 ].…”

“…The tendon mechanical properties (directly related to ECM hierarchical structure) are fundamental for their function. In the force transmission from muscles to tendons, the ratio between the strength of muscular tension and the tendon resistance to tensile force should remain constant (this should be also constant throughout life) [ 9 ] although the aging and other degenerative processes could deteriorate tendon structure [ 30 ].…”

“… Schematic representation of the myotendinous junction (MTJ) and the tendon-to-bone interface (TBI) with its different zones: tendon, fibrocartilage, calcified fibrocartilage and bone. Modified from [ 30 ]. CC BY 4.0.…”