In order to give an organic explanation to all the data collected, as suggested by Fredberg and colleagues [118
], a comprehensive pathogenetic theory may be proposed.
It is well known that well-structured, long-term exercise, well within a physiological range, does not harm the tendon but actually reinforces it, stimulating the production of new collagen fibers. Studies on collagen turnover performed in humans by means of microdialysis techniques show that, after different types of exercise, both synthesis and degradation of collagen are increased, but collagen synthesis prevails and persists longer than collagen degradation [119
]. The tendon tissue becomes larger, stronger and more resistant to injury, with increases in tensile strength and elastic stiffness [122
]. During exercise, both isometric and dynamic, blood flow increases in the tendon and peritendinous area. The biochemical adaptation to exercise is characterized by the release of inflammatory and growth substances, both in the general circulation and locally in tendons: among them is interleukin-1β, which in turn results in the increased expression of Cyclooxygenase-2, MMPs and ADAMTS [123
]. These enzymes are important in regulating cell activity as well as matrix degradation, and they have roles in fiber growth and development.
However, epidemiological observations clearly show that the initial culprit of TP is represented by the overuse of the tendon [52
]. Indeed, TPs are conditions that affect mainly athletes and active people who are involved in activities that stress a specific tendon. When the tendon is overloaded and submitted to repetitive strain, the collagen fibers begin to slide past one another, breaking their cross-links and causing tissue denaturation. This cumulative microtrauma is thought not only to weaken collagen cross-linking but also to affect the non-collagenous matrix as well as the vascular elements of the tendon [124
Moreover, when the tendon is submitted to strenuous exercise, very high temperatures develop inside. Failure to control exercise-induced hyperthermia can result in tendon cell death. Peaks of 43 to 45°C can be reached inside the tendon and experimental studies show that temperatures above 42.5°C result in fibroblast death. This might predispose the tissue for degeneration mainly when, in hypovascular areas, its capability to regulate its inner temperature is hampered. Therefore, there is the possibility that exercise-induced localized hyperthermia may be detrimental to tendon cell survival rather than vascular compromise itself [127
In these conditions, the mechanisms of healing and damage are simultaneously activated. The healing mechanisms include the over-expression of some MMPs, ADAMTs, NOS, GDFs and Scx [63
]; the damage mechanisms are represented by increased MMP-3 expression, which favors the degradation of extracellular matrix, and by the overproduction of inflammatory cytokines, such as endothelial growth factor, platelet derived growth factor, leukotrienes, and PGE2 [6
Given the low metabolic rate of tendons, the optimal conditions for good healing are: adequate recovery time; absence of further overloading; and suitable metabolism and blood supply. When these conditions are not satisfied, the healing mechanisms fail. Unfavorable situations may be represented by predisposing factors (genetic and reduced physiological blood supply in specific areas), or by several risk factors, both extrinsic (heavy sport activities, environmental conditions, training errors in athletes) and intrinsic (age, osteoarticular pathologies, and systemic diseases affecting microcirculation or collagen metabolism). This explains why subjects respond differently to overloading, such that the threshold for repair may vary largely from one subject to another.
Hypoxia induces the production of hypoxia inducible factor, which, in turn, leads to subsequent VEGF expression [109
], which promotes angiogenesis, is able to up-regulate the expression of MMPs, and down-regulates TIMP-3, so altering the material properties of tendon. The invasion of vessels into a region hypovascularized under physiological conditions and MMP expression leads to a weakening of the normal tendon structure. In this phase the subject, albeit showing signs of degeneration and neovascularization at ultrasound evaluation, is usually asymptomatic, even if pain may arise as the result of peritendinitis, which is exquisitely inflammatory in nature (Figure ). When the overload overcomes the thresholds of repair or the tendon is submitted to further loads without adequate recovery time, the healing process fails and the pathogenetic cascade leading to tendinopathy occurs.
Mechanisms of damage. EGF, epidermal growth factor; HIF, hypoxia inducible factor; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; TIMP, tissue inhibitor of metalloproteinase; VEGF, vascular endothelial growth factor.
The transition to the symptomatic phase is usually marked by characteristic histological changes: the invasion of vessels is followed by nerve proliferation, and glutamate levels increase and are responsible for pain during the course of the disease (Figure ). Neo-angiogenesis and nerve proliferation lead to pain when the production of algogenic substances reaches a critical threshold. These substance may further damage the tendon.
From neovascularization to neurogenic inflammation. CGRP, Calcitonin gene related peptide; NMDA-R, N-methyl-D-aspartic acid receptor.
In summary, the pathogenesis of TP is a continuum from physiology to overt clinical presentation. This sequence of events can be compared with an iceberg, having several thresholds, pain being the tip of the iceberg (Figure ). The base of the 'iceberg' represents what happens under physiological conditions. When damage develops, two phases may be recognized: the asymptomatic and symptomatic phases. This definition implies that pain is the alarm symptom: indeed, it is uncommon, with the exception of professional top-level athletes, that tendon abnormalities can be detected earlier by systematic ultrasound evaluation [45
]. It should be noted, however, that the timing of these events may vary considerably due to several individual factors.
Under physiological conditions, exercise increases the strength of the tendon, but when the individual threshold is overcome, microdamage may occur. If the tendon is given adequate time to recover, in good local conditions of blood flow and nutrition, the healing machinery will prevail with complete repair. However, if the recovery time is too short and blood flow is inadequate, the repetitive strain will lead to microdamage inside the tendon (the first phase of TP): a very thin line, indeed, divides healthy and non-healthy physical exercise. Therefore, TP appears to result from an imbalance between protective and regenerative changes and the pathological responses to tendon overuse.
In the second phase, a pathogenetic cascade involving the production of pro-inflammatory cytokines, vascular growth factors, and oxygen free radicals will take place, resulting in degradation of the tendon, neovascularization and possibly nerve proliferation. However, in this phase the subject is still asymptomatic until a new threshold in neovascularization and neural in-growth is reached and pain occurs.
The 'iceberg theory' can thus explain the frequent relapse of symptoms when athletes resume sport activities after too short a rehabilitation period, during which pain recedes to just below the detection threshold while most of the intratendinous abnormalities still exist. Moreover, this theory explains how a complete rupture with evident degeneration may occur in a tendon but still be painless [129