Year: 2003
Type: review
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 or more of the tendon fibre bundles, and strains in excess of 8–12% result in complete tendon rupture. Most overuse tendinopathy is associated with repeated microstrain below the failure threshold, analogous to the fatigue failure that affects most materials placed under repetitive loading. It is generally assumed that tendon matrix damage is the primary event, overwhelming the ability of the resident cell population to repair structural defects. Because cell activity is required for the maintenance of connective tissues, it is equally possible that changes in cell metabolism—more specifically, the synthesis and degradation of the extracellular matrix—can influence the structural properties of the tendon. In other words, changes in cell activity in response to mechanical strain may be primary and not secondary to any physical lesion or ‘micro-injury’. The structure and physical properties of tendon. (A) Collagen (type I) forms rod-like molecules which spontaneously associate with other molecules to form a quarter-staggered array. The overlap and hole zones account for the characteristic banded fibril seen using the electron microscope, due to the differential uptake of electron-dense stains. (B) Bundles of fibrils form fibres, the fibres are bound together by a thin layer known as endotenon, and several fibre bundles are surrounded by an outer layer known as the epitenon. (C) Haemotoxylin and eosin-stained section of normal tendon showing the wave or crimp pattern of the collagen fibres. (D) When strain is applied to a tendon, there is first a straightening out of the crimp, resulting in the ‘toe region’ of the stress–strain curve. Strain within the physiological range causes elastic deformation of the tendon. Higher levels of strain result in partial or complete rupture of fibrils. Actual levels of strain required to induce tendon damage differ in different tendons and are affected by factors such as age and cross-linking of the matrix. This figure can be viewed in colour as supplementary material at Rheumatology Online. It is now recognized that most tendinopathy is rarely associated with any single factor, and the degenerative process that precedes tendon rupture may result from a variety of different pathways and causative factors. Indeed, there is some evidence to suggest that the nature of the degenerative process varies among different sites [5]. Many questions remain about the role of tendon fibroblasts (tenocytes) and other cell types in the disease process. In the absence of an overt inflammatory process, there is no rational basis for the use of anti-inflammatories in chronic tendinopathy, and the source of tendon pain is not understood [31–33]. An objective approach to the treatment of tendinopathy requires a greater knowledge of the tendon matrix and its changes in health and disease. The structure, composition and organization of the matrix are critically important for the physical properties of tendon. The smallest structural unit is the fibril, largely consisting of rod-like collagen molecules aligned end-to-end in a quarter-staggered array [34–36] (Fig. 1A). The fibrils range in diameter from 10 to 500 nm depending on the age, location and species from which the tendon is sampled [37–40]. One or more distinct fibril populations are normally present: a single population of small diameter fibrils in young animals, and a bimodal distribution of small and large diameter fibrils in mature animals [38, 39, 41]. Collagen fibrils aggregate together into fibres, and bundles of fibres (‘fascicles’) are bound together by a thin layer of loose connective tissue known as the endotenon [34] (Fig. 1B). The endotenon carries blood vessels, lymphatics and nerves which generally pass up and down throughout the body of the tendon Bundles of are surrounded by the a structure with the endotenon and in blood vessels, lymphatics and nerves bundles are aligned with the of the tendon and these are for the tensile strength of the tendon. A small proportion of fibres and there are and This and on the tendon. The of the fibre bundles is to the and of the tendon, with small generally found in tendons and large in tendons such as the Achilles The structure is thought to a that failure of one or a few fibre bundles does not the strength of the tendon. bundles a or seen are viewed under (Fig. The out of the crimp for the of the tendon stress–strain which as a fibre damage [29] (Fig. The and length of crimp can in different tendons and at different sites within a tendon This has for the mechanical properties of the as fibres with a small crimp before with a crimp collagen of the mass of the tissue and of the collagen the fibrils are of several different and collagen is the most of the in human supraspinatus and tendons In normal tendons, collagen to be to the endotenon and However, it is found into collagen particularly in tendons and at the insertion sites of tendons such as the supraspinatus collagen to less fibrils this has for the mechanical strength of the tendon. collagen is into the of the collagen fibril, it forms a for and fibril which forms a structure, is to the of the tendon blood collagen forms and is usually found with collagen fibres in normal tendon There is a different distribution in tendon at the collagen is as it is in and are associated with the of the collagen particularly at the insertion These are with with large that are thought to with other matrix found in small in tendon types and thought to be to these are found in the at the they are may to at the tissue in the matrix are by the formation of are by the are two the tissue these with to form mature of the mature been although the are and known as is to and is in small in connective The of in a connective tissue is to its mechanical with the in and which two collagen Tendons a high with other tissues, although there are human supraspinatus tendons the of tendons and collagen the different mechanical demands placed on these tendons A greater of is generally found in tendons, associated with the composition found at these sites However, the does not and these do not to the physical properties of tendons Another form of collagen cross-linking by the process of such as from the circulation to in the matrix There are no and throughout the length of the collagen results in the formation of perhaps better known as are for many of the physical and properties of tissues, such as the in and an on in the a possible cause of some of the cell activities seen in diseases of ageing, such as there are a variety of the is the known as Because the of matrix such as collagen is generally very such as on collagen molecules with the as a of the molecular age of the and this has been in recent of the tendon matrix are a of with many different in the although usually at least one of a of In the of a tendon, and of the tendon The most is and there are small of of the and the a large thought to be a form of the than In of tendons, the of the tendon with a high of and A composition has been described in of and tendons The of in the and the maintenance of synthesis is on The at these sites is a the within the tissue and to in tendon and composition been identified in human tendons In Achilles tendons, and identified in both and at both the and the the large in the tendon with of In the of the Achilles insertion with of in are to the mechanical and of the tendon. Tendons of the of the and the with a of in tendons, which tensile loads higher levels of are found in supraspinatus tendons, with of and These been that is the large together with of This composition is thought to be a result of to the by the supraspinatus tendon in the rotator which the of and may from the and been described in human and tendons thought to be a the formation of may pathological the structural properties and affecting the tendon response to for of may explain tendon are to inflammation in the affects the tendon matrix in a variety of the cell and there is a increase in collagen and a decrease in glycosaminoglycan The collagen changes from to there is no in the collagen which collagen However, the distribution of such as may with a greater proportion into the fibres Collagen fibre bundles to the and the tendon and less elastic There is a decrease in the of thought to be associated with the of such as of these changes may be by although there is some evidence that mature tendons for and are by There is evidence of physical damage in tendons, with in the of collagen and increased of matrix these changes are associated with in the physical properties of the tendon. is associated with increased of degenerative such as of fibre cellularity and increased [6, However, degeneration is not an of ageing, because other tendons may be Tendons from particular such as the and are most to show degenerative which increase in with age and are associated with the high physical demands placed the tendons at these joints both the synthesis and degradation of matrix is important for the maintenance and repair of connective tissues, and tendon is no thought of as and of in been to be throughout the a variety of matrix and However, tendons from different sites and within tendons may be important in tendon disease, as in more the of on Achilles tendon collagen using into the increased formation of by of the There a decrease in the of collagen degradation the but no from at to induce in the human Achilles tendon, at least in The in a which an increased of of collagen synthesis and of but of that the levels of various of and such as 6, and There a increase in and changes in lipid and metabolism as as inflammatory activity of These activities are implicated in the response of tendon, although excessive of some or of these factors may a role in the of tendinopathy as a result of overuse Collagen is to and down and into the matrix it has a with age the collagen and the a of the In the tendon, in a with age, with low levels of collagen in this tendon (Fig. 2). does not at the in supraspinatus tendons, high levels of collagen The increased of with the tendon is thought to be associated with the high levels of strain normally by supraspinatus tendons in The for this activity are particularly as or excessive matrix is a cause of the matrix damage in a of matrix (A) The in a with age in the human tendon. These tendons and the are with very low levels of matrix (collagen) throughout the (B) There is a very of with age in the human supraspinatus tendon. there no of some evidence of degenerative in the tendon The that of the mature collagen has been an individual's from collagen in tendon is with fibroblasts and collagen molecules which are by This is a activity in the although few the of this in tendon. Most on collagen degradation in the extracellular and by of the matrix are some of the few of the collagen in the extracellular at a in the collagen and and is the in collagen and that are in to other such as the with activity and as as the and the The differ in their activities the various although which are implicated in the physiological and pathological of connective tissue is still the subject of of tendon in that is into the and associated with the collagen that usually in An is because of the from the collagen fibril is a for collagen can be by the inflammatory and by the and is associated with increased activity and reduced levels of of in the Factors that activities in tendon are to a role in tendinopathy, as in more are more than the some of the such as can such as in most activity in is associated with a but distinct of known as identified as of the a of and with The to and may to in the matrix. and both at a and in the of the can at the in and may be a has activity the although is known about the for the degradation of other and of from tendon in with to and that of and in both young and mature tendon, with high levels of There no evidence of although not with levels of for or is known about the factors that activities in connective There been few biochemical of chronic tendinopathy, and most been of material at the of the tendon rupture. of supraspinatus tendons found a small but decrease in the collagen and an increased proportion of collagen to collagen of the collagen different with normal and the mature collagen and to a greater than the increased collagen which normally the and of collagen changes been found in animal tendons in chronic tendinopathy and injury by or levels of and the to as healing results in high levels in tissue biochemical an increase in and various in tendons, as yet not There are in the in Achilles tendons, as by changes in properties such as increased in with in the as as small this is evidence for in the tissue increased in tendon, and there of tissue and These matrix changes are with a healing process in the tendon, with or than any The evidence generally the that result in a in the of the tendon matrix. There is a of the from collagen fibrils to a tissue consisting of fibrils and some of the changes found in tendons may be the result of rupture than the there are to that a in collagen precedes and to tendon rupture. A study of the molecular age of the collagen by an of greater levels of matrix in supraspinatus tendons with tendons (Fig. 2). not in a with age, and it that up to of the collagen in the supraspinatus been the (Fig. of in tendons, that a greater proportion of the matrix up to of the in supraspinatus tendons These been by an of the of the of the molecular age of the it that a high of matrix is common in tendons such as the and that this process is to the of degenerative pathology. collagen in supraspinatus tendons associated with the increased and activity of several of the In supraspinatus tendons, and activities higher with normal tendons, which or no collagen In supraspinatus tendons, there increased levels of reduced levels of and and evidence of increased collagen and is thought to be a in the of matrix and a in this may a failure in the normal process. tendinopathy may result from a failure to repair or the tendon matrix in response to mechanical strain or repeated A study of from the of patients with rotator cuff pathology high levels of of both and in patients with tendons, with no in the levels of and the levels of with the of levels higher in from with partial with increased of matrix at the of the in supraspinatus and increased in The of matrix in tendon pathology in a molecular study of Achilles tendinopathy using of that and in tissue The absence of inflammation within the tendon and there large in the of matrix such as collagen and The and but there no in such as and in and the with biochemical In to matrix there changes in and in normal tendon. The normal and pathological in the of in the of which or less in painful tendinopathy and tendon of not in normal tendons or in chronic tendon Because and are normally the in is an interesting that is yet to be It is possible that activity is required for normal tendon at least in tendons, such as the supraspinatus and the The of activity in tendinopathy account for the increase in found in tendon as these are for the However, more is required to the role of other such as the and in tendon pathology. The important role of in tendon pathology is by the of two very different a of matrix found to induce a painful tendinopathy in usually in the or are required to which activities are an or can induce tendinopathy in some patients and these been to at least in on a of activity by with In of human we a small of by In with the of on both and and there a increase in synthesis of Because may inflammatory pathways in or the tendon the on tendon matrix may account for the of tendinopathy in some many hypotheses and in studies, the factors that induce pathological matrix in tendinopathy not been There is evidence that cell activities are in chronic tendon in tendons evidence of changes and levels of increased in the of patients with Achilles tendinopathy, with increased activity There evidence of increased in rotator cuff tendons higher than in cell in the pathology mechanical strain and and molecules but a few may a on activity and the of tendon matrix and and of such as been to in tendon are of the of activities and matrix at least in inflammatory such as not been in the tendon there greater of in the of patients with rotator cuff with with although the degree of pain with the levels of The a in the of increased in tendinosis, and there increased of factor cellularity at the of the tendon lesion associated with the levels of of factor and from lesions increased of cell and a greater response to with normal tendon of inflammation and vascular perfusion that are by such as and may a role Because and other been in tendon and in from painful tendons there is evidence for a of tendon overuse injury (Fig. and may as to tendon and to mechanical as a result of overuse may result in pathological changes to the tendon matrix. In of this has been to the of several tendon matrix and including although the precise on and of tendon ‘overuse’ (A) and in the matrix as in the tendon matrix. The of such as and the of a of which a variety of cell activities in the matrix. (B) and cell to and in the normal tendon, although excessive to tissue and from A study of in the Achilles that one in the matrix of both normal and pathological tendons increased in Achilles tendinopathy, the absence of one of the with the that not place in the tendon. failure to matrix degradation may result from failure to in response to This that the of factors such as to tendon repair may be in chronic It is with the that the chronic nature of tendinopathy represents a failure to cell activities repair or matrix there are no for tendinopathy that specifically this of tendinopathy are by the absence of animal models that the chronic seen in of equine tendon lesions damage with changes in the matrix to described in human tendinopathy to tendon lesions in animals using been generally less of to activity can induce changes in the and degeneration of the tendon although these lesions difficult to been used in and as has the of or inflammatory such as of with can induce tendon with inflammation of the preceding degenerative changes in the tendon matrix Because these can by tendon this may about the disease The role of has been in animal in any one of the small or with collagen and tendon of has been used to increase the diameter of collagen fibres in healing and this approach may some in the treatment of tendon the mechanical properties of the tissue with a collagen that collagen to tendons than and the tendon insertion to with the of collagen at least the of healing in the although the on tendon healing not been models of tendon pathology with are to important on the role of matrix and in tendon and disease. The tendon matrix is to its the of from to It is not a and the matrix to the and of the applied a process of by the tendon The tendon matrix is throughout although higher of are found at sites to high levels of or such as the Achilles and the changes in tendon pathology be to intrinsic such as changes in cell activity with age, or extrinsic such as repetitive strain and In tendon there is an increased of matrix leading to a different and less tendon, which is to tendon degeneration may result from a failure to activities in response to repeated injury or mechanical Whether tendon repair can be of the factors matrix in tendon. These factors mechanical and of which been implicated in the of tendon and The has no of
Source: Rheumatology
Author: G. Riley
Institution: Addenbrooke's Hospital
Language: English
Subfield: Orthopedics and Sports Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2133419930