The Biology of Tendon Pathology

Tendons and ligaments belong to a family of "dense connective tissues" that serve important roles in vivo in connecting functioning parts. Tendons connect muscles to bones and thus transmit significant repetitive loads during joint motion. They also stabilize joints during all activities in which both gravity and external loads must be overcome. In contrast to most ligaments, tendons normally operate in the linear region of their stress-strain curves due to the fact that they are active structures under the influence of muscle forces.

In this article, we will review research on tendon structures and functions that are of particular interest to orthopaedic surgeons.

Tendons Are Complex, Heterogeneous Structures

Despite appearing to be simple, tendons are surprisingly complex structurally and heterogeneous, likely due to the variety of environments in which they are required to function (Thornton and Hart, 2011). As with nearly all soft connective tissues, tendons subscribe to the “use it or lose it” paradigm (Hart et al, 2002) and require mechanical loading to maintain homeostasis. In the absence of mechanical loading, tendon tissues undergo atrophy, due in part to derepression of proteinases (Hart et al, 2002; Arnoczky et al, 2004, 2008).

To resist the very high, repetitive loads that they must carry, tendons normally contain a very high proportion of densely packed collagen fibers (mainly collagen I) organized in a nearly parallel fashion, spaced by water. Tendons also contain several types of collagen, and the collagen is organized to carry high loads and cross-linked to resist fatigue failure from repetitive loads. Recent studies have indicated that tendons also express lubricating molecules such as hyaluronic acid, and the boundary lubricant, lubricin/PRG4 (Sun et al, 2006), which may play a role in tendon function (Kohrs et al, 2011).

Several other types of proteoglycans bind water and help bridge collagen fibers, serving important functions in transmitting loads and other biochemical signals between surprisingly inter-connected tendon cells. At birth, tendons are cell-rich and matrix poor, a situation that is reversed at skeletal maturity. However, the matrix-producing cells in tendons and ligaments are connected into a network via specialized gap junctions in spite of the cells appearing to be well separated when assessed in H&E stained sections (discussed in Chi et al, 2005). Disruption of such cellular networks due to excessive cell death (eg, apoptosis, necrosis) by overuse or overt injury could be detrimental for optimal functioning of the affected tendon over time.

Tendons have a blood supply (generally more near insertions and more on their surfaces), as well as nociceptive (pain) and proprioceptive (position sense) nerves in these same locations. Nerves and blood vessels clearly have important biologic and physiologic effects (reviewed in Ackermann et al, 2009). The nerve supply is believed to serve regulatory functions in normal tendon function via release of neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP). SP and CGRP may also play roles in healing and responsiveness to excessive loading (Salo et al, 2007; Ackermann et al, 2009; Bring et al, 2009, 2012).

Tendons have very complex insertion sites onto muscles at one end (the myotendinous junction) and into bones at the other end, with complicated transitions of their structures through a zone of fibrocartilage into mineralizing fibrocartilage before their fibers enter and are embedded in bone. The cells near and at the insertions are different, likely modified by the local loading environment to produce different matrix to prevent damage and failure of the tendon at very high stress locations. In addition to the above-indicated transitions in tendons, in those tendons that traverse around a boney prominence, the normal alignment of collagens designed to address tensile loads transition to compositions and orientations that address compressive loads (Vogel et al, 1993; Vogel, 2004).

Not all tendons are the same. As described by Boyers et al (2001), there are two big sub-families of tendons: those with and those without a synovial covering. The synovial covering lubricates interfaces, but it also provides a relative barrier to vascular and cellular in-growth. In addition, some tendons (eg, the flexor tendons) move through a tendon sheath during their normal range of motion. This has important implications for damage, for repair, and for the healing of damaged tendons. Tendons are not all equally likely to be damaged, nor are they equally likely to heal. This is well known in and around the hand, but it is also true with all other joints in the body. For those tendons that migrate through a sheath, injury to the tendon and/or the sheath can lead to adhesions as a consequence of the healing process, adhesions that can impede movement and compromise tendon function.

In addition to “internal” regulation of tendons and their function due to different environments, tendon homeostasis or response to injury can also be influenced by external factors such as co-morbidities (eg, diabetes, cardiovascular diseases), exposure to compounds (eg, some antibiotics) and drugs (eg, statins) (Sode et al, 2007; Carmont et al, 2009; Stinner et al, 2010), gender-related factors (eg, estrogens, androgens, and progesterone), and other hormones (eg, glucocorticoids). Tendons express sex-hormone receptors and, therefore, could be influenced by relevant hormones after puberty, during the menstrual cycle, or during pregnancy and by their loss following menopause (discussed in Thornton and Hart, 2011).

Another “variable” affecting tendon function is aging. Tendons are known to become stiffer with age, but not all individuals of a given age are affected equally (genetics and/or history?). It is clear that a general ability to initiate and complete effective repair declines with age, and thus, aging of tendons may reflect impaired repair processes or age-dependent loss of stem cells that could mediate aspects of effective repair.

Finally, tendon function and risk for injury appears to also be related to genetic factors, although the mechanisms involved remain largely ill-defined at this juncture (Bring et al, 2012). For example, only a subset of patients taking certain antibiotics or statins develop tendon pathology, mainly the Achilles tendon (Sode et al, 2007) and the basis for such sensitivity is not known. In addition, it is known that only a subset of individuals engaged in an athletic activity develop tendon pathology, and it is likely that genetic risk plays a role in the overall risk.

Tendons and Tendon Cells Exhibit Sensitivity to Loading Changes

Each tendon operates within a “physiological window” designed for that individual tendon (Thornton et al, 2010). Loading that is less than the homeostatic set point can lead to defined atrophy until a new set point is established. Event-related loading that is grossly in excess of the physiological window leads to traumatic failure of tendon integrity with the need for overt repair. Within these two extremes are repetitive loading patterns of sufficient extent, or without allowance for endogenous repair which lead to development of “overuse syndromes” that can affect the tendon proper, or associated tissues such as the paratenon of the Achilles tendon.

Tendon fibroblasts are particularly sensitive to changes in tendon loading conditions, responding with metabolic changes in their synthesis and degradation of the matrix molecules that make up the functioning tendon. Load deprivation of a tendon is particularly damaging to the tendon matrix, dramatically decreasing matrix synthesis and increasing matrix degradation (disruption of the anabolic/catabolic balance).

Interestingly, excessive tendon loading can also be damaging to a tendon, but this is certainly not a simple matter of breaking the collagen fibers and mechanically damaging the tendon matrix. Excessive loading can certainly fail the tendon matrix and result in loss of collagen load-carrying ability. Higher-than-normal loads may also, however, simply alter cellular expression within the tendon and, similar to the situation described above associated with immobilization, create an environment that favors high matrix turnover with a propensity to matrix degradation.

If there is enough load to drive sufficient gross local physical matrix damage, it can potentially trigger local inflammation (red/hot/tender/swollen changes locally), with secondary vascular in-growth and scar-like repair reactions. If loads are not that high or prolonged enough to cause gross collagen fatigue damage, matrix can apparently become damaged by local cellular processes without local secondary inflammatory changes.

This process has been called "tendinosis" (without local inflammation) as opposed to "tendonitis" (with inflammation) (Khan et al, 2002; reviewed in Brukner and Khan, 2006). Tendinosis and tendonitis have been studied in both human biopsies and in animal models (Archambault et al, 2001) in an attempt to better understand the pathologic causes, signs, symptoms, and mechanisms of "tendinopathy" and to propose more effective treatment and prevention strategies. Programmed cell death caused by high local matrix strains (Scott et al, 2005) may be one cause of tendinopathy.

Summary

Tendons are complex at the molecular, cellular, organizational, and environmental levels. They are regulated by internal and external factors across the lifespan, with mechanical loading a dominant factor with modulation by biologic variables. Loss of tissue integrity and/or development of painful tendons can contribute significant morbidity and quality of life to a large subset of the population, particularly those engaged in certain activities and as they age.

References

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Archambault J.M., Hart D.A., Herzog W. Response of rabbit Achilles tendon to chronic repetitive loading. Connect Tissue Res. 2001;42(1):13-23.

Arnoczky SP, Tian T, Lavagnino M, Gardner K. Ex vivo static tensile loading inhibits MMP-1 expression in rat tail tendon cells through a cytoskeletally based mechanotransduction mechanism. J Orthop Res. 2004;22:328-33.

Arnoczky SP, Lavagnino M, Egerbacher M, Caballero O, Gardner K, Shender MA. Loss of homeostatic strain alters mechanostat “set point” of tendon cells in vitro. Clin Orthop Relat Res. 2008;466:1583-91.

Boyer M.I., Gelberman R.H., Burns M.E., Dinopoulos H., Hofem R., Silva M.J. Intrasynovial flexor tendon repair. An experimental study comparing low and high levels of in vivo force during rehabilitation in canines. J Bone Joint Surg Am.


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Bring DK, Reno C, Renstrom P, Salo P, Hart DA, Ackermann PW. Joint immobilization reduces expression of sensory neuropeptide receptors and impairs healing after tendon rupture in a rat model. J Orthop Res. 2009;27:274-80.

Bring DK, Paulson K, Restrom P, Salo P, Hart DA, Ackermann PW. Residual substance P levels after capsaicin treatment correlate with tendon repair. Wound Repair Regen. 2012;20:50-60.

Brukner P and Khan KM, eds. Clinical Sports Medicine, 3rd Edition, McGraw-Hill, 2006.

Carmont MR, Highland AM, Blundell CM, Davies MB. Simultaneous bilateral Achilles tendon ruptures associated with statin medication despite regular rock climbing exercise. Phys Ther Sport. 2009;10:150-2.

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Kohrs RT, Zhao C, Sun YL, Jay GD, Zhang L, Warman ML, An KN, Amadio PC. Tendon facicle gliding in wild type, heterozygous and lucbricin knockout mice. J Orthop Res. 2011;29:384-9.

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Scott A., Khan K.M., Heer J., Cook J.L., Lian O., Duronio V. High strain mechanical loading rapidly induces tendon apoptosis: an ex vivo rat tibialis anterior model. Br J Sports Med. 2005 May;39(5):e25.

Sode J, Obel N, Hallas J, Lassen a. Use of fluroquinolone and risk of Achilles tendon rupture: a population-based cohort study. Eur J Clin Pharmacol. 2007;63:499-503.

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Thornton GM, Shao X, Chung M, Sciore P, boorman RS, Hart DA, Lo IK. Changes in mechanical loading lead to tendon –specific alterations in MMP and TIMP expression: Influence of stress deprivation and intermittent hydrostatic compression on rat supraspinatus and Achilles tendons. Br J Sports Med. 2010;44:698-703.

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Reprinted with permission from the Fall 2010 issue of COA Bulletin; expanded by Drs. Frank and Hart in July 2012