The pathogenesis of tendinopathy. A molecular perspective

Abstract

There are many publications that discuss the aetiology, diagnosis and treatment of the various forms of tendinopathy, but few are based on conclusive scientific evidence. The pathogenesis of tendinopathy is difficult to study because tendon biopsies are rarely obtained before a tendon has ruptured. There are interesting comparisons with animal tendinopathy, particularly in the equine athlete, although many animal models do not accurately reflect the human condition—the tendon lesions usually heal. However, the application of biochemical and molecular techniques to the study of both animal and human tendinopathy has led to a greater understanding of these common and disabling conditions. This article summarizes current knowledge of the pathogenesis of tendinopathy, with particular emphasis on the molecular pathology of the tendon matrix. Tendons may be affected by a variety of different pathological conditions. Many systemic diseases are associated with general defects in matrix metabolism and structure that compromise tendon strength and elasticity, or result in inflammation of the tendon or its insertion [1–3] (Table 1). These conditions are not the subject of this review, although they must be considered as part of the differential diagnosis. Systemic diseases affecting tendon Systemic diseases affecting tendon Tendonitis (or tendinitis) is the term traditionally used to describe a chronic painful tendon, and assumes that tendon injury is accompanied by an inflammatory response. This is contrary to the evidence from histopathological, biochemical and molecular studies, and the lesion is perhaps better described as a ‘tendinosis’ [4–9]. However, as we cannot exclude the possibility that inflammation is implicated at some stage in the condition, the term ‘tendinopathy’ is used throughout this article to describe disorders primarily affecting tendons, including tendon rupture and chronic pain. Unlike tendonitis and tendinosis, this term does not assume any knowledge about the underlying pathology. Another term in frequent use is ‘spontaneous tendon rupture’, used to describe ruptures that occur without any preceding clinical symptoms [5, 10]. Because healthy tendons can withstand very high tensile loads—much higher than required for their normal function—these conditions are rarely truly spontaneous and are associated with at least some degree of matrix degeneration [10, 11]. The precise nature of the degenerative process is still the matter of debate. There are a variety of degenerative features associated with tendinopathy, including glycosaminoglycan (GAG) accumulation, calcification and lipid accumulation. However, many of these features are found in normal tendons and are not necessarily pathological [5, 6, 12–14]. Tendinopathy can be associated with a variety of both intrinsic and extrinsic factors (Table 2). High body mass and constitutional factors such as leg-length discrepancies can place tendons under excessive or abnormal patterns of loading [15, 16]. A sedentary lifestyle allied with the particular physical demands of occupation or sporting activities may account for the increased incidence of tendon rupture in recent times. The influence of an individual's sex and genetic background is unknown, although some association with genetic factors has been postulated in a proportion of patients [15, 17]. Laxity of the joints may be a predisposing factor for patella tendinopathy and rotator cuff lesions [15]. Gene defects affecting tendon (collagen) fibre formation and metabolism may explain some of these conditions, although as yet no defect has been identified that is specifically associated with tendinopathy [1]. Factors implicated in chronic tendinopathy Factors implicated in chronic tendinopathy The literature is dominated by two hypotheses on the cause of tendon rupture—a mechanical theory and a vascular theory—but the two are not mutually exclusive. Many lesions are associated with low or reduced vascular perfusion in tendons such as the supraspinatus and Achilles [15, 18–21]. A decrease in circulation may occur as a result of ageing, vascular disease, physical disuse or trauma, leading to tissue hypoxia and reduced viability of the tendon cells. However, in apparent contradiction of this theory, chronic tendon lesions often show an increase in vascularity and increased cellularity [6, 13], a so-called angiofibroblastic response [22], and there is an increase in the tendon blood flow [23, 24]. Whether this represents evidence of a healing response, secondary to the initial lesion, is uncertain [24]. Many painful tendon lesions are thought to be the result of repetitive microtrauma, frequently described as ‘overuse’ pathologies [16, 25–28]. This is often explained with reference to the biomechanical properties of tendon and the stress–strain curve [29] (Fig. 1). Physiological loads usually cause less than a 4% increase in the length of the tendon [26, 30]. Strain above 4% results in damage to one