Multiscale molecular interactions of tendon

Tendon does not exist in isolation, but is sandwiched between two other metabolically and mechanically active tissues—bone and muscle—and is sometimes in close proximity to a synovial environment, and, thanks to the vasculature, is bathed in a milieu of mediators potentially derived from all other tissues. Thus, tendon is tightly integrated to its environment across multiple levels throughout the lifespan, from the intrinsic and extrinsic exposome to the molecular level, all interacting with the mechanical environment. All these factors can be investigated in varying degrees of complexity with modeling and experimental work. This is the theme of the current Special Issue of Connective Tissue Research. As always when examining common threads in a group of related manuscripts that appear on first look to be linked by keywords such as “tendon,” “collagen,” or “extracellular matrix,” more questions are raised than answered. Collagen fiber diameter has received substantial attention in the tendon field, but collagen fiber length is still somewhat of an unfolding mystery. Mehdizadeh et al. (1) continue their development of much-needed modeling approaches to predict the tissue-level secretion profile of anabolic molecular factors such as active TGF-β in response to nonuniform collagen fiber length distributions and the influence of time delays in the repair of damaged collagen fibers. Critically, this model predicts that the anabolic responsiveness to tendon loading (increasing strain and number of cycles) is reduced when collagen fiber lengths are widely dispersed, and when repair is delayed. The model also predicts that when collagen fiber lengths have low dispersion, tendon stiffness is increased. Continuing the collagen fiber theme, but focusing on collagen-collagen interactions across the multiscale, Eekhoff et al. (2) review the current literature relating to the contributions of native enzymatic and nonenzymatic cross-links to tendon mechanical properties. The gaps in current knowledge relating to how cross-linking impacts the mechanical properties of individual tendons across the length scale are eloquently discussed, and the importance of considering not only quasistatic, but also viscoelastic testing in these studies is highlighted. The current hypothesis that nonenzymatic cross-links are predominantly located on the fiber surface, inhibit interfiber sliding, and cause loss of viscous response and increase in modulus on the tendon scale is discussed. Interestingly, while increased stiffness of tendons with aging has been reported by several groups, and there is general agreement that mature collagen fibrils are “long” (>1 mm), the exact fibril length in adult tendon is more controversial, with mechanical data supporting discontinuous fibers throughout the tendon length, and high-resolution structure investigations favor continuous long fibers throughout the tendon (3). While maintaining responsiveness to anabolic factors is clearly desirable under conditions of widely dispersed collagen fiber lengths, or when repair is delayed, how can experimental data from crosslinking studies and modeling data be reconciled in light of recent structural studies? Continued advances in high-resolution structural imaging underloading conditions, and further refinements to models will answer these questions. Two exciting new models that will answer key questions in rotator cuff tendinopathy are characterized here (4,5). An elegant ex vivo explant model using the intact mouse supraspinatus muscle-tendon-interface bone unit will be useful moving forward following further refinement to improve viability in culture (4). This model could be used to answer crucial questions surrounding bone-tendon-muscle cross talk, including the source and role of proand anti-inflammatory cytokines in injury to the rotator cuff unit, and will allow investigation of other circulating mediators, for example myokines that to date have not been well studied in tendon. A valuable new in vivo partialwidth full-thickness injury to the insertion of the infraspinatus tendon in the rotator cuff by Lemmon et al. (5) confirmed that these injuries can heal, albeit by fibrosis. Further studies using this model will be critical to understanding the limitations and properties of this innate healing process, and will provide new avenues to test potential pharmacological or engineered solutions. Existing models were also used to evaluate cross talk within tendon to systemic disease (6) and to induction of tendon cell stress in localized tendinopathy (7). At first look the findings of these two studies appear to be CONNECTIVE TISSUE RESEARCH 2018, VOL. 59, NO. 5, 393–395 https://doi.org/10.1080/03008207.2018. 1514801