Chronic Tendon Pathology: Molecular Basis and Therapeutic Implications

http://www.expertreviews.
org/
expert reviews
in molecular medicine
Chronic tendon pathology: molecular basis

and therapeutic implications
Chronic tendon pathology: molecular
basis and therapeutic implications
Graham Riley
Tendons are frequently affected by chronic pain or rupture. Many causative
factors have been implicated in the pathology, which until relatively recently
was under-researched and poorly understood. There is now a greater knowledge
of the molecular basis of tendon disease. Most tendon pathology (tendinopathy)
is associated with degeneration, which is thought to be an active, cell-mediated
process involving increased turnover and remodelling of the tendon
extracellular matrix. Degradation of the tendon matrix is mediated by a variety
of metalloproteinase enzymes, including matrix metalloproteinases and
‘aggrecanases’. Neuropeptides and other factors released by stimulated cells
or nerve endings in or around the tendon might influence matrix turnover, and
could provide novel targets for therapeutic intervention.
Tendons are dense, fibrous connective tissues that has been called tendinosis (Refs 2, 3, 4, 5, 6, 7, 8). In
connect muscle to bone and are essential for the this review, the term tendinopathy is used for all
transmission of force and the generation of forms of chronic tendon pathology, because it does
movement at a joint. They are highly ordered not assume any knowledge of the underlying
composite materials consisting of collagens, pathology.
proteoglycans and various glycoproteins, many
of which have been poorly characterised. Tendon Factors implicated in tendinopathy
problems such as tendon rupture and chronic It is increasingly recognised that most
tendon pain are common, although the tendinopathies are not associated with any single
underlying pathology is not well understood and factor, and tendon degeneration might result from
the conditions are often difficult to treat (Ref. 1). various causes. Indeed, there is some evidence to
Terms such as tendonitis (or tendinitis) are suggest that the nature of the degenerative process
traditionally used to describe a painful tendon, varies at different sites (Ref. 3). Tendons at certain
the name implying an inflammatory condition. sites are more commonly affected, particularly the
This is contrary to the evidence from most supraspinatus, extensor carpi radialis brevis,
histopathological studies, which describe a patellar and Achilles (at the shoulder, elbow, knee
degenerative condition without inflammation that and ankle, respectively) (Refs 9, 10). These tendons
Graham Riley
Head of Soft Tissue Injury and Repair Group, Rheumatology Research Unit, Box 194, Addenbrooke’s
Hospital, Hills Road, Cambridge, CB2 2QQ, UK. Tel: +44 (0)1223 217458; Fax: +44 (0)1223 217838;
E-mail: [email protected]
Institute URL: http://www.addenbrookes.org.uk
1
Accession information: DOI: 10.1017/S1462399405008963; Vol. 7; Issue 5; 24 March 2005
©2005 Cambridge University Press
http://www.expertreviews.org/
expert reviews

are all exposed to relatively high mechanical
demands, although additional factors are thought
to be important. The majority of patients present
in late middle age, often with no memory of any Tendon
Epitenon
acute injury or trauma (Refs 10, 11). The condition
Tertiary fibre bundle
usually has an insidious onset, with pain
developing during or shortly after exercise.
Secondary fibre
Tendon ruptures often occur during physical
bundle (fascicle)
activity, typically in sports such as badminton
(Ref. 12). Many cases of tendinopathy are ascribed
to ‘overuse’, thought to result from repeated
microstrain below the failure threshold, analogous Endotenon
to the fatigue failure that affects most materials
placed under repetitive loading (Refs 10, 13, 14, 15).
It is generally assumed that tendon damage
is the primary event, overwhelming the ability Primary fibre
of the tendon cells (generally referred to as bundle (subfascicle)
tenocytes) to repair structural defects in the tendon Collagen fibre
extracellular matrix (ECM). Alternatively, there is
Collagen fibril
thought to be a failure to adapt to a change in
physical demands. Tenocytes have a central role
in the repair and maintenance of the tendon ECM, Structure of tendon
synthesising new proteins and producing the Expert Reviews in Molecular Medicine 2005
enzymes that degrade them. This continual Published by Cambridge University Press
process of matrix turnover is normally in balance,
and changes in this activity in response to altered Figure 1. Structure of tendon. Tendon consists of
patterns of loading, for example, might precede a highly ordered hierarchy of successively larger
any physical lesion or ‘micro-injury’. Aside from structural units. Collagen molecules aggregate into
microtrauma and hypoxia, factors that could fibrils, and bundles of fibrils form fibres, many of
potentially affect the tenocyte activity include age, which are aggregated into primary fibre bundles or
temperature, drugs and the local activity of subfascicles. Multiple subfascicles form secondary
biochemical mediators produced by the resident fibre bundles or fascicles, and several fascicles form
cells. The potential roles of some of these factors tertiary fibre bundles. Most tendons consist of
are discussed in this review, which emphasises multiple fascicles, which is thought to be a fail-safe
mechanism so that failure of one or more fibre
the importance of ECM turnover and matrix-
bundles does not compromise the tendon strength.
degrading enzymes in tendon health and disease.
Fibre bundles are surrounded by a thin layer of
connective tissue known as the endotenon, through
The structure and function of tendon which pass blood vessels, lymphatics and nerves.
The principles of tendon structure and function The whole tendon is bound by another thin layer
have been comprehensively reviewed elsewhere (contiguous with the endotenon) known as the
(Refs 16, 17, 18, 19, 20). In general, tendon consists epitenon. A loose outer layer known as the paratenon
of successively larger structural units assembled surrounds most tendons (not shown), and some
in a highly ordered hierarchy of collagen molecules, tendons are also surrounded by a specialised
microfibrils, subfibrils, fibrils, fibres and fascicles synovial sheath. Figure modified from Ref. 21 (© 1978);
(fibre bundles) (Ref. 21) (Fig. 1). However, tendon reproduced by permission of Taylor & Francis, Inc.,
http://www.taylorandfrancis.com.
is not a homogenous tissue: there are variations
in structure and composition between tendons
and at specific sites within tendons (Ref. 20). similarities in structure and composition with
The best-characterised regional variation articular cartilage, although it also retains essential
within tendon is fibrocartilage, which is found at characteristics of fibrous connective tissue. Its
the insertion or where a tendon bends around a main function is to dissipate shear stress or resist
bony prominence or through a fibrous pulley compression, and the fibrocartilaginous region
(Refs 20, 22, 23). Fibrocartilage shares some can vary greatly in size depending on factors such
2
expert reviews

as the range of movement and the angle of insertion synthesising activity compared with the tenocytes
(Refs 24, 25). Fibrocartilage is also thought to play within the fibres, and are the first cells to respond
a role in the migration of the insertion during after acute tendon injury (Refs 28, 29, 30, 31, 32).
skeletal growth, and to prevent narrowing of the Fibrochondrocytes from the fibrocartilaginous
stretched tendon at the interface with bone (Ref. 20). zones synthesise different matrix components (see
The cell population in tendon is poorly below), an activity that is stimulated and
defined, and there is no single marker of tenocytes maintained by the application of compressive load
(Refs 26, 27). The majority of cells have the (Refs 33, 34, 35). A small proportion of cells are
appearance of fibroblasts, although there are also thought to be mesenchymal stell cells, capable of
chondrocyte-like cells (fibrochondrocytes) within differentiating into chondrogenic, osteogenic and
fibrocartilaginous zones, and a small number of adipogenic cells when cultured in the appropriate
capillary endothelial cells, smooth muscle cells conditions (Ref. 27).
and nerve cells, depending on the degree of
vascularity and innervation (Ref. 18). There are The molecular composition of tendon
regional differences in cell morphology and Tendon is a highly ordered composite material
activity within tendons. Synovial-like cells found consisting predominantly of collagen, with
in the endotenon and epitenon surrounding the smaller amounts of various proteoglycans and
main fibre bundles (Ref. 28) possess a greater glycoproteins, many of which are relatively
proliferative capacity and a different matrix- poorly characterised (Table 1). Although many
Table 1. Molecular composition of tendon extracellular matrix

Molecule Structure/type Location and function
Collagen
Type I Fibril-forming Main constituent of tendon (~95% of total collagen)
Type II Fibril-forming Restricted to fibrocartilage; forms less-organised meshwork
Type III Fibril-forming Normally restricted to endotenon; forms smaller, less-organised fibrils
Type IV Forms meshwork Basement membrane of blood vessels
Type V Fibril-forming Core of type I collagen fibril; forms template for fibrillogenesis
Type VI Beaded filaments Cell-associated; found in ‘seams’ between fibrils
Type IX FACIT Mediates cell–matrix interactions with type II collagen fibril surface
Type X Forms meshwork Restricted to insertion fibrocartilage; associated with mineralisation?
Type XI Fibril-forming Core of type II collagen fibril; forms template for fibrillogenesis
Type XII FACIT Mediates cell–matrix interactions with type I collagen fibril surface
Type XIV FACIT Mediates cell–matrix interactions with type I collagen fibril surface
Proteoglycan
Decorin SLRP Binds collagen, affects collagen-fibril formation, binds growth factors
Biglycan SLRP Binds collagen, affects collagen-fibril formation, binds growth factors
Fibromodulin SLRP Binds collagen, affects collagen-fibril formation, binds growth factors
Lumican SLRP Binds collagen, affects collagen-fibril formation
Aggrecan Hyalectan Resists compression; most prominent in fibrocartilage
Versican Hyalectan Lubricates boundary between adjacent fibrils?
Glycoprotein
Elastin Branched network Forms elastic fibres; provides elastic properties of tissue
Fibrillin Linear arrays Forms elastic fibres; provides elastic properties of tissue
Tenascin-C Branched molecule Mediates cell–matrix interactions; forms ‘seams’ with versican
COMP Branched molecule Mediates cell–matrix interactions; role in fibril formation?
Fibronectin Modular protein Mediates cell–matrix interactions; role in tendon healing
Laminin Modular protein Component of basement membranes
Link protein Globular protein Stabilises proteoglycan–hyaluronan interactions
Thrombospondin Modular protein Mediates cell–matrix interactions
Abbreviations: COMP, cartilage oligomeric matrix protein; FACIT, fibril-associated collagen with interrupted
triple helix; SLRP, small leucine-rich repeat proteoglycan.
3
expert reviews

constituents of tendon are present in very small collagen forms beaded microfilaments. Type VII
amounts, they have important roles in the ECM, collagen is essentially restricted to basement
including modulating the formation of fibrils membranes where it forms anchoring filaments.
and mediating cell–ECM interactions. It is Several collagens have transmembrane domains,
important to emphasise that the ECM does not including types XIII, XVII, XXIII and XXV, which
merely fulfil a passive, structural role: many of mediate interactions between the cell and its
its constituents also have an impact on tenocyte external environment. Some collagens, designated
activity. Tendon is not an inert material, as the FACIT (for ‘fibril-associated collagens with
ECM can be continuously synthesised and interrupted triple helix’), are associated with the
replaced throughout life, although the rate of surface of fibrils and have several interruptions
metabolism is much lower than in tissues such as in the triple-helical structure. Collagen types IX,
muscle and bone (Ref. 36). There is also evidence XII and XIV are the archetypal FACITs, although
of variation in the rate of turnover at different sites the more recently described collagen types XVI,
and in different tendons (Refs 37, 38). This activity XIX, XX, XXI, XXII and XXVI are thought to be
is likely to be influenced by both internal and related members.
external factors, and is potentially a major factor The fibril-forming type I collagen is the major
in the development of tendinopathy. component of tendon; it is generally estimated to
represent 95% of the total collagen, although it is
Collagen difficult to be precise because of its insolubility,
Extensive reviews of the synthesis, structure and particularly in ageing tendon specimens (Ref. 47).
function of collagen, particularly of collagen types Type III collagen is the next most abundant
I–XIX, have been published elsewhere (Refs 39, collagen in tendon, forming around 3% of the total
40, 41, 42, 43, 44). In brief, each collagen consists in human supraspinatus and biceps brachii
of three polypeptide α-chains, which combine tendons (Ref. 47). In normal tendon, most type III
together as a homotrimer (three identical α-chains) collagen is found in the endotenon and epitenon
or a heterotrimer (with two or three different (Ref. 48), although it is also found intercalated into
α-chains). To date, 42 vertebrate α-chains have the type I collagen fibril bundles, particularly in
been sequenced, several of which can be ageing tendons and at the insertion (Ref. 49).
differentially spliced, and these combine to form Other minor constituents of tendon are collagen
at least 27 different collagens (Refs 39, 40, 44). Each types IV, V, VI, XII and XIV. Collagen types II, IX,
α-chain forms an extended left-handed helix, and X and XI, once thought to be restricted to cartilage,
contains a variable length of the repeated amino are found in the fibrocartilaginous regions of
acid motif Gly-X-Y, where X and Y are commonly tendons and ligaments, where they are presumed
proline and hydroxyproline. This amino acid to function to help resist compression and shear
composition is an absolute requirement for the forces at these sites (Refs 50, 51).
formation of the right-handed triple helix, a
defining characteristic of collagenous (COL) Proteoglycans
protein domains. The collagens also possess ECM proteoglycans have been classified into two
globular, noncollagenous (NC) domains of subfamilies: the small leucine-rich repeat
variable size, number and location. proteoglycans (SLRPs) and the large modular
Although all collagens form highly organised proteoglycans. The latter are further divided into
polymers, the different collagen types can be two subgroups: those that do not bind
grouped according to whether they form fibrils hyaluronan; and the ‘hyalectans’, which bind both
or other structures such as extended sheets or hyaluronan and lectin (Refs 40, 52, 53). Only the
lattices. The classic fibril-forming collagens (types SLRP and hyalectans are considered in this review,
I, II, III, V and XI) comprise a single COL domain since these are the most abundant proteoglycans
for almost the entire length of the molecule, with in the tendon ECM.
small NC domains at each end (Fig. 2). The newly
discovered collagen types XXIV and XXVII have SLRPs
a similar molecular structure (Refs 45, 46). The SLRPs are found in most connective tissues and
nonfibrillar collagens are a heterogenous group include decorin, biglycan, fibromodulin and
with a variety of structures. Collagen types IV, VIII lumican. They all possess a small protein core
and X form extensive networks, whereas type VI (36–42 kDa), with an N-terminal domain for
4
expert reviews

Figure 2. Synthesis of a fibril-forming collagen.
a Assembly of three procollagen chains (a) Following synthesis, the three collagen α-chains
undergo extensive post-translational modification,
Glc including hydroxylation of lysine residues and
Gal Mann
GlcNAc glycosylation. (b) The α-chains wrap around each
O OH
OH other to form a tightly wound, right-handed triple
SH
OH OH OH SH helix which is secreted as a procollagen monomer.
OH OH SH (c) The N- and C-terminal propeptides are cleaved
OH SH by specific peptidases. (d) The processed collagen
OH
forms multimolecular aggregates, which are aligned
O
Gal end-to-end to form banded fibrils. (e) Crosslinks
are formed between specific amino acids, which
stabilise the collagen fibril and provide tensile
strength. Abbreviations: Gal, galactose; Glc, glucose;
b Assembly of triple helix Mann, mannose; GlcNAc, N-acetylglucosamine;
OH, hydroxyl group; SH, sulphydryl group. Figure
modified from Ref. 44 (© 2004), with permission
from Elsevier.
c Cleavage of propeptides carry one to four chains of GAG, which can be

keratan sulphate (KS), dermatan sulphate (DS)
or chondroitin sulphate (CS). The type of GAG
depends on the tissue, with decorin containing CS
in bone and DS in tendon (Ref. 55). Fibromodulin
and lumican have a similar protein core structure
d Assembly into collagen fibrils to decorin, but contain KS. (Ref. 56).
The most abundant proteoglycan in tendon is
decorin, although biglycan is also present in small
amounts (Ref. 57). All the SLRPs are now thought
to have some role in collagen-fibril formation
(fibrillogenesis), acting in a sequential and
orchestrated fashion during development and
repair to control the growth and ultimate diameter
e Formation of covalent cross-links of the collagen fibres (Refs 58, 59). Decorin, for
example, is found attached to collagen fibres at
specific sites every 64–68 nm, where it acts to
modulate (limit) collagen-fibril formation
(Refs 60, 61). Modulation of this activity using
antisense gene therapy to inhibit decorin gene
transcription has been shown to promote the
Synthesis of a fibril-forming collagen formation of larger collagen fibrils in healing
Expert Reviews in Molecular Medicine 2005 ligament, thus improving the strength of repair
Published by Cambridge University Press (Ref. 62). Biglycan binds only weakly to type I
collagen and has a much greater affinity for type
Figure 2. Synthesis of a fibril-forming collagen. VI collagen, promoting the rapid formation of
(See next column for legend.) hexagonal networks (Ref. 63).
Apart from their role in ECM organisation, the
binding of glycosaminoglycan (GAG) chains, a SLRPs can also modulate various cell activities
central region of leucine-rich repeats flanked by (Refs 64, 65, 66). Decorin, fibromodulin and
clusters of cysteines, and a C-terminal domain biglycan, for example, might modulate the activity
(Ref. 52) (Fig. 3a). The protein core is compact of the resident cell population by binding to and
and horseshoe shaped, which might be important sequestering growth factors such as transforming
for protein–protein interactions (Ref. 54). SLRPs growth factor β (TGF-β) (Refs 65, 66).
5
expert reviews

Figure 3. Proteoglycans in tendon. (a) Small
a SLRPs leucine-rich repeat proteoglycans (SLRPs). SLRPs
Decorin in tendon include decorin, biglycan, fibromodulin
and lumican. They share a common core protein
structure with ten leucine-rich repeats (LRRs) and at
least one chain of glycosaminoglycan (GAG).
Decorin in tendon has one dermatan sulphate (DS)
Biglycan chain, whereas biglycan has two chondroitin
sulphate (CS) chains. Fibromodulin and lumican
have up to four keratan sulphate (KS) chains and
some tyrosine (Tyr) residues are sulphated. Part a
of figure reproduced, with permission, from the
Fibromodulin Glycoforum website (http://www.glycoforum.gr.jp).
(b) Hyalectans. The hyalectans in tendon are versican
and aggrecan, with versican predominant in tensile-
loaded regions and aggrecan in compressed,
fibrocartilaginous regions. All hyalectans contain a
Lumican G1 domain, a GAG-attachment region and a G3
domain that has similarities with selectin. Aggrecan
also has a G2 domain, separated from G1 by an
interglobular domain (IGD), and the molecule
contains approximately 100 CS chains and 30 KS
chains. Versican contains up to 21 CS chains,
b Hyalectans clustered within two GAG domains known as GAGα
and GAGβ. One or both of the GAG domains might
Aggrecan be removed by alternative splicing of the mRNA
KS CS1 CS2 transcript, forming four versican splice variants.
The ‘hyalectans’
The hyalectan subgroup of large proteoglycans
comprises aggrecan, versican, brevican and
G1 G2 G3 neurocan (Refs 40, 52). Neurocan and brevican
IGD are thought to be restricted to brain and neural
tissues. The hyalectans possess a large protein
Versican core (100–370 kDa) consisting of a C-terminal
GAGα GAGβ
domain with epidermal growth factor (EGF)-like
repeats, a central domain carrying the majority
of GAG chains, and an N-terminal hyaluronan-
binding domain (Ref. 56) (Fig. 3b).
Aggrecan, the major proteoglycan of articular
cartilage but also found in tendon, forms
G1 G3 multimolecular aggregates with the nonsulphated
GAG hyaluronan. Aggrecan is reported to be
present throughout tendon, although it is
CS/DS KS N-glycan Cys TyrSO4 generally thought to be more abundant in regions
of fibrocartilage. Aggrecan has three globular
Core protein LRR domains (G1, G2 and G3) and contains many GAG
chains (CS and KS) attached to specific sites in
Proteoglycans in tendon the GAG-binding domain between the G2 and G3
Expert Reviews in Molecular Medicine domains (Ref. 67). The high fixed negative charge
C 2005 Cambridge University Press (part b only) of the GAG attracts counter-ions and functions to
hold water within the tissue. Swelling of the
Figure 3. Proteoglycans in tendon. (See next tendon is restrained by the collagen meshwork,
column for legend.) and the resulting turgor functions to resist
6
expert reviews

compressive load. Thus, the expression of Tenascin-C is a disulphide-linked hexameric
aggrecan in compressed regions of tendon, or protein with subunits of 200–300 kDa in humans,
areas subjected to shear forces such as the created by alternative splicing of a single gene
insertion, is thought to be a functional adaptation transcript (Refs 82, 83). In normal fibrous tendon,
that protects the tissue from damage. tenascin-C might have a role in maintaining the
Versican has been identified in many soft interface between fibrils and adjacent structures
connective tissues and has a similar structure to (Ref. 84). In fibrocartilaginous regions of tendon,
aggrecan, although it lacks a G2 domain and tenascin-C is predominantly cell-associated
contains much less GAG, all of which is CS (similar to type VI collagen) and is implicated in
(Ref. 68). Its precise role in tendon is unknown, the development of the chondrocyte cell phenotype
although it is found associated with seams of (the expression of type II collagen and aggrecan)
microfibrils between fibres and it might in response to compressive load (Ref. 84).
function to facilitate the sliding of adjacent fibre Tenascin-C is transiently increased after tendon
bundles. injury, and is thought to modulate cell activities
in the developing scar (Refs 85, 86).
Glycoproteins Cartilage oligomeric matrix protein (COMP),
The noncollagenous components of tendon are despite its name, is not restricted to cartilage and
relatively poorly characterised. Elastin, thought is a major component of tendon, representing up
to make up less than 2% of the tendon dry weight, to 3% of the dry weight (Ref. 87). A member of the
is a component of the elastic fibres that are thrombospondin gene family (thrombospondin 5),
thought to maintain the tendon crimp and to be it is a large (524 kDa) pentameric molecule
responsible for the elastic properties of the ECM composed of five disulphide-bonded subunits
(Refs 13, 69). Fibrillin is also a major component (Ref. 88). Like tenascin-C and the other
of the elastic microfibril, and is thought to form a thrombospondins, it is thought to have both a
template for tropoelastin and the assembly of the structural role and an interactive role with the cell
elastin multimer (Refs 70, 71). Elastic microfibrils population. There is a strong positive correlation
are present in most connective tissues and contain of COMP expression with the levels of mechanical
polymers of fibrillin-1 and fibrillin-2 (Refs 70, 71). load, with higher levels in flexor tendons
Mutations in fibrillin-1 have been linked to compared with extensors (Ref. 89). Levels of
Marfan’s syndrome and associated disorders of COMP increase with age up to skeletal maturity,
various connective tissues (Ref. 72). Fibrillin-1 is although only in weight-bearing tendons (Ref. 89).
associated with type XVI collagen in the dermis The structural importance of COMP is shown by
(but not in cartilage), and other proteins such as the condition of pseudoachondroplasia, a genetic
versican, fibulin, matrix-associated glycoprotein disorder caused by a mutation in the COMP gene,
(MAGP)-1, MAGP-2 and emilin (Refs 73, 74, 75, 76). resulting in short stature, lax joints and early-onset
The microfibril structures that are formed have osteoarthritis (Ref. 90).
been divided into essentially three types on the basis In addition to serum proteins such as albumin,
of structure and appearance – oxytalan, elaunin other glycoproteins in tendon include: laminin,
and elastic – which differ in the relative amounts which is found as a major constituent of basement
of elastin (from lowest to highest, respectively). membranes; link protein, which stabilises
Elastic fibres, predominantly oxytalan, are hyalectan–hyaluronan interactions (Refs 6, 91);
reportedly more homogenous and abundant in and other multidomain adhesive glycoproteins,
developing tendon, less common in adult tendon including members of the thrombospondin
and absent from fibrocartilage (Ref. 77). family, that, like COMP, tenascin and fibronectin,
Fibronectin mediates cell interactions with mediate cell–matrix interactions in normal and
the ECM, and affects a range of cell functions injured tissues (Refs 92, 93, 94).
including cell adhesion, cell migration,
differentiation, haemostasis, phagocytosis and The molecular pathology of chronic
chemotaxis (Refs 40, 78). Present at low levels in tendinopathy
normal tendon, fibronectin is massively increased Histopathological studies of tendinopathy have
after tendon injury and consequently has been shown an absence of inflammatory cell infiltration
implicated in cell adhesion, migration and and the presence of many features thought to be
differentiation at the site of injury (Refs 79, 80, 81). characteristic of ECM degeneration. These include
7
expert reviews

a loss of fibre organisation, decreased fibril collagen (Ref. 47). The collagen had a high
diameter, changes in cell density (both increased content of hydroxylysine and there were greater
and decreased), cell rounding, GAG accumulation, than normal levels of the mature collagen
lipid accumulation and calcification (Refs 3, 4, 5, crosslinks hydroxylyslpyridinoline (HP) and
7, 95) (Fig. 4). Although similar changes are lysylpyridinoline (LP) (Ref. 97). These and other
commonly found in normal tendons, they are crosslinks greatly affect the solubility of the
generally less severe, and it is assumed that ECM collagen, making it difficult to assess the collagen
degeneration precedes the onset of the clinical type, even using chemical methods such as
condition (Refs 3, 7, 96). cyanogen bromide peptide mapping. However,
There have been few biochemical studies of the changes in the tendon ECM are characteristic
chronic tendinopathy. In ruptured supraspinatus of scar tissue, and the levels of type III collagen
tendons there was a small but significant decrease and HP tend to diminish as healing proceeds,
in the total collagen content, and an increased although high levels often persist because of
proportion of type III collagen relative to type I incomplete remodelling (Ref. 98). Similar ECM
a b
c d
Histopathology of tendinopathy
Expert Reviews in Molecular Medicine C 2005 Cambridge University Press (parts a, b and d only)
Figure 4. Histopathology of tendinopathy. (a) Normal flexor tendon histology, showing organised parallel
fibre bundles and long thin tenocytes dispersed throughout the matrix [stained with hematoxylin and eosin
(H&E)]. (b) Ruptured supraspinatus tendon, showing hyaline (glassy) appearance, loss of matrix organisation
and rounded, shrunken nuclei (H&E). (c) Glycosaminoglycan (GAG) accumulation (‘mucoid degeneration’) in
supraspinatus tendon, showing GAG (blue) surrounding rounded cells in the matrix (Alcian Blue and H&E).
(d) ‘Angiofibroblastic’ change in painful Achilles tendinopathy, showing increase in cell number and blood
vessels (H&E). Part c of figure reprinted from Ref. 4 (© 1994); reproduced with permission from the BMJ
Publishing Group.
8
expert reviews

changes have since been reported in studies of example, that the tendon fails to recover after the
posterior tibialis tendon dysfunction and Achilles inflammatory reaction has subsided.
tendon rupture (Refs 99, 100). These data are In summary, the ECM changes described in
consistent with the gradual accumulation of type chronic tendinopathy are consistent with a cell-
III collagen over a relatively long time period, mediated remodelling process occurring in
allowing the maturation of collagen crosslinks degenerate tendon, without inflammation. The
and stabilisation of the ECM. The gradual process is similar in many respects to the later
incorporation of type III collagen into the main stages of a wound-healing response, albeit with
fibre bundles is consistent with a reduction in the impaired or incomplete remodelling, rather than
average fibril diameter (Ref. 101), a change that is any functional adaptation. The evidence generally
thought to weaken the tendon and to precede supports the hypothesis that there is gradual
tendon rupture (Ref. 102). deterioration in the quality of the ECM, which
Other biochemical studies have shown an predisposes to tendon pathology. A key element
increase in the amount of hyaluronan and various of this process is thought to be the cellular
proteoglycans in degenerate tendons, although expression of proteolytic activities and their effects
the latter have not yet been fully characterised on tendon ECM turnover.
(Refs 103, 104). An increased water content,
typically 10% above normal, is commonly found Role of MMPs in tendon collagen
in tendinopathy, associated with the increased degradation and tendinopathy
proteoglycan content. Consequently, the specimen Proteolytic activity is an essential component of
dry weight or collagen (hydroxyproline) content tissue maintenance and repair. After injury,
is a better reference point for composition studies proteolysis is required to remove any damaged
than the tissue wet weight. Differences in the ECM and remodel the newly formed scar so
sugar moieties expressed in ruptured tendons that it more closely resembles the normal tissue.
compared with normal were revealed by Some collagen in tendon is probably degraded
changes in lectin-staining properties (Ref. 105). intracellularly after phagocytosis, with fibroblasts
Glycoproteins such as tenascin-C were increased and macrophages engulfing collagen molecules
in ruptured supraspinatus, with different that are then digested by lysosomal enzymes,
protein isoforms expressed as well as numerous comprising mainly cysteine and aspartate
small peptide fragments, the latter consistent proteases (Refs 111, 112). This is a major activity
with enzyme-mediated cleavage in the tissue in the rapidly remodelling peridontal ligament,
(Ref. 84). Fibronectin immunostaining was although few (if any) studies have investigated
significantly increased in ruptured tendon, and the function of lysosomal enzymes and serine
there was accumulation of necrotic tissue and proteases in tendon matrix turnover. Most
fibrin (Ref. 106). published studies have focused on collagen
Several studies have shown differences in the degradation occurring in the extracellular
expression of various genes encoding matrix environment and mediated by secreted
proteins in tendinopathy (Refs 107, 108, 109). In metalloenzymes known as the MMPs.
one study, for example, 23 genes were found to
be upregulated and 17 genes were downregulated MMPs: a brief overview
in degenerate Achilles tendon (Ref. 107). Although Comprehensive reviews of the MMPs have been
potentially very informative, relatively few of published elsewhere and only salient points are
these changes have been confirmed by more reviewed here (Refs 113, 114, 115, 116, 117, 118,
rigorous techniques, and the levels of cognate 119, 120). MMPs are members of the ‘MB’ clan of
proteins for many of these genes have not been metallopeptidases, generically referred to as
investigated. There were no changes detected in ‘metzincins’ because they contain zinc at the active
the expression of cytokines and cytokine site and a conserved methionine eight residues
receptors, consistent with the absence of any downstream. There are 23 MMPs found in
ongoing inflammatory process, as confirmed by humans, each comprising a multidomain
an analysis of the fluids surrounding painful structure and with activity at neutral pH against
tendons (Ref. 110). However, these data do not a broad spectrum of different ECM substrates
rule out the involvement of inflammation at (Refs 114, 116, 118) (Table 2; Fig. 5a). Although
earlier stages of the disease. It is possible, for important in ECM degradation, MMPs also have
9
expert reviews

Table 2. Major known or putative substrates of the matrix metalloproteinases
Family/type MMP Descriptive name(s) Principal or major known
substrates
Collagenases MMP-1 Interstitial collagenase 1 Fibrillar collagens types I, II, III

MMP-8 Neutrophil collagenase
MMP-13 Collagenase 3
Gelatinases MMP-2 Gelatinase A, 72 kDa gelatinase Nonfibrillar collagens, gelatin

MMP-9 Gelatinase B, 92 kDa gelatinase
Stromelysins MMP-3 Stromelysin 1, transin Proteoglycans, fibronectin, laminin,

nonfibrillar collagens, pro-IL-1,
collagen type III
MMP-10 Stromelysin 2, transin-2
Matrilysins MMP-7 Matrilysin, PUMP-1 Proteoglycans, link protein, fibronectin,

MMP-26 Matrilysin 2, endometase laminin, nonfibrillar collagens, gelatin,
fibrin, entactin
Elastase MMP-12 Macrophage elastase, Elastin, nonfibrillar collagens

metalloelastase
Transmembrane MMP-14 MT1-MMP Pro-MMP-2, (MMP-13), gelatin, tenascin,

fibronectin, vitronectin, aggrecan
MMP-15 MT2-MMP
MMP-16 MT3-MMP
MMP-24 MT5-MMP
GPI anchored MMP-17 MT4-MMP Pro-MMP-2, gelatin

MMP-25 MT6-MMP
Miscellaneous MMP-11 Stromelysin-3 α1-Proteinase inhibitor, IGFBP-1

MMP-19 RASI-1 Gelatin, aggrecan, COMP, fibrin, tenascin
MMP-20 Enamelysin Amelogenin, aggrecan, COMP
MMP-21 xMMP Not known
MMP-23A CA-MMP Gelatin
MMP-23B Not known
MMP-27 MMP-22, cMMP Gelatin, casein
MMP-28 Epilysin Not known
Abbreviations: CA, cysteine array; cMMP: chicken MMP; COMP, cartilage oligomeric matrix protein; GPI,
glycosylphosphatidylinositol; IGFBP-1, insulin-like growth factor binding protein 1; MBP, myelin basic
protein; MMP, matrix metalloproteinase; MT, membrane-type; pro-IL-1, pro-interleukin 1; PUMP, putative
metalloproteinase; RASI-1, rheumatoid arthritis synovium inflamed 1; TNF, tumour necrosis factor; xMMP,
Xenopus MMP.
activity against cell-surface receptors and growth cytokines such as interleukin 1 (IL-1) and tumour
factor precursors (Ref. 119). Consequently, these necrosis factor (TNF), and is inhibited by growth
enzymes also have an important role in the factors such as TGF-β. MMPs are potently
regulation of numerous cellular activities inhibited by α2-macroglobulin in the serum, and
including cell proliferation, cell death (apoptosis), also by a family of specific inhibitors produced
cell migration and chemotaxis (Ref. 119). by cells within the tissues known as tissue
The activities of MMPs are normally tightly inhibitors of metalloproteinases (TIMPs) (Refs 115,
controlled in vivo, with regulation at the levels of 116, 121). Four TIMPs have been characterised to
gene transcription, protein translation, activation date, and each TIMP binds to active MMPs in a
and inhibition. In general, expression and activity stoichiometric (1:1) ratio, resulting in a stable,
of the MMPs is stimulated by pro-inflammatory inactive complex.
10
expert reviews

a Collagenate and gelatinase MMPs
Signal
Propeptide peptide
C
Collagenases, stromelysins and
other MMPs: MMP-1, MMP-8, MMP-13, Zn2+
MMP-3, MMP-10, MMP-12, MMP-19, Haemopexin
domain
MMP-20, MMP-27
Catalytic
domain Hinge
region
Gelatinases: MMP-2, MMP-9 Zn2+
Type II
fibronectin
repeats
b ADAMTS
Signal
Propeptide peptide
TS
repeat Spacer
Zn2+
Disintegrin-like Cys-rich TS repeats

MMP-like catalytic domain region (variable number)
domain
Domain structure of matrix metalloproteinases (MMPs) and ADAMTS

Expert Reviews in Molecular Medicine C 2005 Cambridge University Press
Figure 5. Domain structure of matrix metalloproteinases (MMPs) and ADAMTS. (a) MMPs. The archetypal
MMPs such as the collagenases and stromelysins share common domains: a signal peptide that is cleaved
prior to synthesis, a propeptide that renders the enzyme inactive until removed by proteolysis, a catalytic
domain with a zinc-binding site, a hinge region, and a haemopexin domain that confers substrate specificity.
Gelatinases have an additional, gelatin-binding domain consisting of fibronectin type II repeats. Other MMPs
have additional domains (not shown, but see Ref. 120). (b) ADAMTS. The ADAMTS family share a common
domain structure, with a prodomain that is cleaved within the cell to activate the enzyme, a metalloproteinase
catalytic domain, a disintegrin domain, a cysteine (Cys)-rich domain and a variable number of thrombospondin
(TS) type I repeats. Several additional C-terminal domains have been found downstream of the variable TS
type 1 repeats in some ADAMTS molecules (not shown, but see Ref. 120). Modified figure reproduced from
Ref. 120, published in this journal.
MMPs in tendon implicated in the remodelling of tendon that

The MMPs are implicated in both the physiological follows immobilisation (Refs 126, 127, 128, 129).
and pathological turnover of the tendon ECM. MMP-1 is thought to be one of the key mediators
Pieces of normal tendon placed in explant culture of tendon fibrillar collagen degradation, at least
produce collagenase and gelatinase activities, in explant culture, and this activity can be
degrading the collagen matrix after two to three inhibited by the application of cyclical strain, an
weeks in culture, and this process is stimulated effect though to be mediated via the tenocyte
by the addition of inflammatory cytokines such cytoskeleton (Refs 130, 131, 132, 133, 134). Isolated
as IL-1 (Refs 122, 123, 124, 125). MMPs are also tenocytes respond to strain and shear forces by
11
expert reviews

upregulation of MMP, demonstrating that The greatest difference between normal and
mechanical strain is likely to be a major stimulus pathological tendon specimens was the level of
for ECM remodelling in tendon (Refs 135, 136). MMP-3, which was absent or significantly less
MMP expression was stimulated in rabbit abundant in painful tendinopathy (Refs 107, 108).
tendon in vivo by extended periods of cyclical A similar change was reported in degenerate
loading, although there was no sign of injury as supraspinatus tendons (Ref. 38), consistent with
assessed by histological examination (Ref. 137). a role for MMP-3 in the maintenance of the normal
Intense physical training was also shown to tendon ECM, at least in highly stressed tendons
increase MMP-2 and MMP-9 activities in the fluid such as the supraspinatus and the Achilles. The loss
surrounding human Achilles tendon (Ref. 138). of MMP-3 activity in tendinopathy could account
Several MMPs have been identified in acute for the increase in proteoglycan commonly found
tendon injuries, with differences in the timing and in tendon lesions, since proteoglycans are
location of expression that suggest different roles potential substrates for the enzyme. However,
in the healing process. Levels of MMP-9 and since most proteoglycan degradation in vivo is
MMP-13 peaked 7–14 days after injury, whereas attributed to aggrecanases (see below), more
MMP-2, MMP-3 and MMP-14 increased and were research is required to identify the role of MMP-3
maintained at high levels until at least day 28 in tendon.
(Ref. 139). Thus, it appears that MMP-9 and
MMP-13 are involved in the degradation of Role of aggrecanases in tendon
collagen in the initial inflammatory phase, proteoglycan degradation and
whereas MMP-2, MMP-3 and MMP-14 have a role tendinopathy
in the remodelling of the scar tissue. Proteoglycans are turned over much more rapidly
A comparison of human tendons showed than the fibrillar collagens. Although some
evidence of substantial differences in the rate of members of the MMP family, for example
collagen turnover between tendons from different MMP-3, can degrade proteoglycans such as
sites (Ref. 38). There was very little collagen aggrecan in vitro, most proteoglycan-degrading
turnover in normal biceps brachii tendons, activity in vivo is associated with a related but
which contained no significant levels of MMP distinct group of metallo-endopeptidases,
activity and a linear accumulation of pentosidine commonly known as aggrecanases.
crosslinks with increasing age (Ref. 38). By Aggrecanases were first identified on the basis
contrast, supraspinatus tendons obtained from of their ability to cleave aggrecan at specific Glu-
normal shoulders showed relatively high levels of Xaa bonds. The core protein is cleaved at several
collagen turnover, and there were correspondingly sites, resulting in the shortening of the core protein
high levels of MMP-1, MMP-2 and MMP-3 or the complete loss of the GAG-rich portion of
activity (Ref. 38). In ruptured supraspinatus the molecule from the tissue (Ref. 142). This
tendon, there was increased activity of MMP-1, activity was associated with the loss of cartilage
reduced activity of MMP-2 and MMP-3, and proteoglycan that accompanies osteoarthritis
evidence of increased turnover of the collagen (Ref. 143). Aggrecanases were subsequently
network (Ref. 38). Levels of expression of MMP-1 identified as members of the ADAMTS family, a
and MMP-3 in shoulder fluids were shown to subgroup of ADAM (for ‘a disintegrin and
correlate with the size of the tendon tear, and metalloproteinase’) with thrombospondin (TS)
MMP-1 was expressed by cells within the type I motifs (Refs 144, 145) (Fig. 5b).
ruptured tendon (Refs 140, 141).
Studies of painful Achilles tendons using Aggrecanases and the ADAMTS family
cDNA arrays have identified several differences To date, 19 mammalian ADAMTS enzymes have
in MMP gene expression, although many of these been identified, many of which are not yet fully
findings need to be confirmed by RT-PCR analysis characterised (Refs 144, 145). ADAMTS-2,
(Refs 107, 108). The absence of MMP-1 and MMP-8 ADAMTS-3 and ADAMTS-14 are procollagen
expression was consistent with an absence of peptidases, and function as regulators of collagen-
inflammation, and there was a small but variable fibril assembly (Refs 146, 147, 148). ADAMTS-4
increase in MMP-2 and MMP-14 in degenerate (aggrecanase 1) and ADAMTS-5 (aggrecanase 2)
tendons, whereas MMP-9 and MMP-13 were were the first aggrecanases to be identified (Refs
detected only in ruptured tendons (Refs 107, 108). 144, 149, 150), although ADAMTS-1 and other
12
expert reviews

phylogenetically related enzymes (ADAMTS-8, Aggrecanase activities in tendon
ADAMTS-9, ADAMTS-15 and ADAMTS-20) Studies of normal (bovine) tendon have shown
might also have aggrecanase activity (Refs 151, that proteoglycans are constitutively turned over
152, 153, 154). Best known for their activity against relatively rapidly, with hyalectans breaking down
aggrecan, ADAMTS-1 and ADAMTS-4 are also more rapidly than the SLRPs (Refs 167, 168, 169).
capable of cleaving other ECM proteoglycans such Proteolytic fragments of proteoglycans such as
as versican and brevican (Ref. 155), and aggrecan were present in both young and mature
glycoproteins such as COMP (Ref. 156), at least tendon, in both tensional and compressed regions.
in vitro. Although inhibition of ADAMTS-4 and Much of the aggrecan in tendon appears to lack
ADAMTS-5 can prevent cartilage degradation in the G1 domain, but the molecule might be
tissue culture models (Ref. 157), the enzymes retained in the tissue by interactions of the G3
responsible for proteoglycan degradation in domain with an unidentified matrix component.
osteoarthritis and other diseases of connective Cultured tendon explants released cleavage
tissues have yet to be identified. products into the culture medium and there was
Aggrecanase activity is thought to be regulated no significant stimulation of this activity by IL-1
at multiple levels, although the mechanism is (Ref. 167). There was no evidence of MMP-
currently poorly understood. Differential mediated proteoglycan turnover, although
regulation of ADAMTS mRNAs has been aggrecan turnover did not directly correlate with
deduced from analysis of their expression in cell the levels of expression of either ADAMTS-4 or
and explant cultures, albeit with considerable ADAMTS-5 mRNA. However, gene expression
variation between studies (Refs 157, 158, 159, 160, might play a relatively minor role in the regulation
161). A study of human tendon cells has reported of aggrecanase activity, and further studies are
small and variable effects of IL-1 on ADAMTS-4 required to identify the enzyme activities
expression (Ref. 161). present in human tendon and their role in
In addition to regulation at the level of gene tendinopathy. Since levels of proteoglycan are
transcription, the activities of ADAMTS enzymes increased in the degenerate tendon lesion (unlike
are also subject to post-translational regulation. osteoarthritic cartilage), it will be interesting to
The noncatalytic ancillary domains of ADAMTS-4 determine whether this is caused by an increase
are required for both catalytic activity and in proteoglycan synthesis or a decrease in
substrate specificity (Refs 162, 163). Full-length proteoglycan degradation.
enzyme is sequestered in the ECM via GAG-
binding sequences in the spacer domain, and Clinical implications
sulphated GAGs attached to the aggrecan core Anti-inflammatory drugs: do they have a
protein are required for ADAMTS-4 activity role in the treatment of tendinopathy?
(Ref. 163). Deletion of the C-terminal spacer The absence of inflammatory cells, at least at later
domain increased the efficiency of hydrolysis of stages of the disease, would suggest that there is
aggrecan at Glu373-Ala374 bonds, and revealed no rational basis for the treatment of chronic
new activities against fibromodulin, decorin and tendinopathy with anti-inflammatories such as
a general protein substrate (Ref. 163). Several short nonsteroidal anti-inflammatory drugs (NSAIDs)
forms of ADAMTS-4, thought to be generated by and corticosteroid injections, both of which are
autocatalytic C-terminal truncation, are found in commonly used even though there are limited
cartilage, and these potentially contribute to the data to demonstrate their effectiveness (Ref. 1).
degradation of a broad range of protein substrates However, it has recently been argued that the
in addition to proteoglycans (Refs 162, 163). The definition of inflammation should be reappraised,
enzymes are thought to be secreted in an active since inflammatory mediators can be produced
form after cleavage of the prodomain within by a variety of cell types, and not just by
the cell by furin, which might be followed by infiltrating leukocytes (Ref. 170). Degenerative
C-terminal truncation by MMP-17 at the cell surface conditions such as osteoarthritis can be considered
(Refs 164, 165). Aggrecanases such as ADAMTS-4 inflammatory diseases on this basis, with the
are inhibited by the general proteinase inhibitor expression of cytokines and nitric oxide by
α2-macroglobulin and by the specific endogenous chondrocytes and/or synovial cells (Refs 170, 171,
inhibitor TIMP-3, but not by other TIMPs 172). In a similar fashion, it is possible that
(TIMP-1, -2 and -4) (Ref. 166). mediators of inflammation might be involved in
13
expert reviews

chronic tendinopathy, although produced by the precise cause of the syndrome remains
the resident cell population or surrounding unidentified. Additional activity against
connective tissues (Refs 173, 174, 175, 176). For ‘sheddases’ (members of the ADAM family of
example, prostaglandins and other inflammatory metalloproteases involved in the processing of
mediators were found to be increased in the fluids cell-surface receptors) might explain the
surrounding tendons following vigorous exercise development of the syndrome, although there is
and are implicated at least in the adaptive no consensus of opinion. Because there are many
response of the tissue (Refs 177, 178, 179). different enzymes, a solution to this problem will
Increased expression of the inducible require an analysis of all the metalloproteinase
cyclooxygenase (COX-2) in patellar tendinosis enzymes that are expressed and active in healthy
suggests some involvement of prostaglandins in and degenerate tendon.
the disease (Ref. 175). Several studies have shown
IL-1 was more abundant in the endotenon, Neuropeptides and tendon ECM turnover:
vascular endothelium and synovial tissues a novel therapeutic target for tendinopathy?
surrounding affected tendons (Refs 174, 176). If inflammation is not associated with the
Inflammatory mediators might also be transiently development of chronic tendinopathy, other
produced by the tenocytes, which can be induced causes of tendon pain and ECM degeneration
to express IL-1β and COX-2 under the influence must be considered. Recent studies have
of mechanical strain, providing a theoretical basis suggested that nerves, and small peptides
for the development of ‘overuse’ tendinopathy (‘neuropeptides’) produced by nerve endings,
(Refs 180, 181, 182, 183). However, most molecular might have a role in tendinopathy, similar to that
studies of tendinopathy have so far provided no described in intervertebral disc degeneration (Refs
conclusive evidence for the involvement of 189, 190).
inflammatory mediators and cytokines such as In studies of ‘tennis elbow’ lesions, nerve
prostaglandin E2 and IL-1 (Refs 107, 108, 184, 185). endings and neuropeptides were found at the site
of the lesion, although it was unclear if this
Enzymes as potential targets for therapy distribution was different to normal (Ref. 191).
In degenerative conditions such as osteoarthritis, Studies of fluids obtained from around painful
one of the targets for drug therapy is the increased tendons using a microdialysis technique have
cartilage ECM degradation mediated by enzymes shown that levels of the neurotransmitter
such as MMPs and ADAMTS (Refs 118, 186). glutamate were significantly increased in
Various therapeutic approaches have been tendinopathy relative to controls (Refs 110, 184,
attempted, including selective inhibition of 192). Both free glutamate and glutamate receptors
collagenases or broad-spectrum inhibition of (NMDAR1) have also been detected within
many different MMPs, although none has yet been Achilles tendons, located to nerve fibres, both in
successful in clinical trials (Ref. 118). tendinopathy specimens and in controls (Ref. 193).
The pathology of tendinopathy is evidently Since glutamate is a potent mediator of pain in
different from osteoarthritis, with increased cell the central nervous system, it was suggested that
activity, neovascularisation, and accumulation of NMDAR1 antagonists might be useful in the
proteoglycan within the lesion, in addition to treatment of tendon pain.
increased turnover of the matrix collagen. Indeed, It has also been reported that substance P,
it would appear that some ECM turnover is another neuropeptide associated with the sensation
required for maintaining the health of the tendon, of pain, is increased in the subacromical bursa in
at least in highly stressed tendons such as the patients with rotator cuff tendinopathy (Ref. 194).
supraspinatus and Achilles. This hypothesis is The amount of substance P was shown to correlate
consistent with data obtained from clinical trials with the degree of motion pain as assessed by a
with broad-spectrum MMP inhibitors, which were visual analogue scale. Whether this was due to
found to cause an unwanted side effect described an increase in the release of substance P or an
as a ‘musculo-skeletal syndrome’ in the tendons increase in the number of nerve fibres was not
of the patients’ shoulders and hands, which clear, although immunohistochemistry showed
recovered after the cessation of therapy (Refs 187, more nerve fibres in bursal tissues of patients with
188). Compounds selective for collagenases or a perforated rotator cuff (Ref. 194). Apart from the
gelatinases did not induce the condition, and modulation of pain, substance P and other
14
expert reviews

neuropeptides might have additional effects, enzymes, including MMPs and aggrecanases.
regulating the local circulation and stimulating Some enzymes are thought to be responsible for
neurogenic inflammation in and around the repair and maintenance of the tendon, and others
tendon (Refs 195, 196). are implicated in the pathological destruction of
Hart et al. have proposed that regulatory units the ECM: these enzymes need to be identified so
composed of nerve endings and mast cells reside that new drugs can be developed. There are a
in and around the tendon (Ref. 197). The release variety of factors that might influence ECM
of neurotransmitters stimulates mast-cell turnover in tendon, although a major factor in
degranulation, releasing a variety of mediators most tendinopathy is thought to be repeated
including growth factors that influence oedema, minor mechanical strain or ‘overuse’. Although
angiogenesis, fibroblast proliferation and many infiltrating inflammatory cells are probably not
other aspects of cell activity. Biomechanical involved in chronic tendinopathy, neuropeptides
stimulation of these nerve–mast-cell units might and other mediators of pain and inflammation
form part of the normal regulatory system, produced in or around the tendon might be
maintaining the tissue and also contributing to implicated, and could provide novel targets for
the adaptive response to load. Excessive therapeutic intervention.
stimulation of neural–mast-cell units might
contribute to overuse tendinopathy. Since the Acknowledgements and funding
extent of innervation and vascularisation varies The author is grateful for financial support from
between different tendons, the potential for the the Arthritis Research Campaign, The Isaac
development of neurogenic dysfunction also Newton Trust, REMEDI, The Wishbone Trust, The
varies. This theory potentially links mechanical Dunhill Medical Trust, The Sybil Eastwood Trust
stimulation of the paratenon, which is more and the Cambridge Arthritis Research Endeavour
richly innervated, and tissue changes in the (CARE). Acknowledgements are due to many past
tendon mid-substance. The association of and present members of the Rheumatology
neuropeptides with tissue remodelling has not Research Unit, in particular Dr Brian Hazleman,
been conclusively proved, although substance P Professor Tim Cawston, Dr Michael Chard, Dr
and calcitonin-gene-related peptide (CGRP) were Steven Fenwick, Dr Anthony Corps, Mrs Val
shown to modulate directly the expression of Curry and Ms Rebecca Harrall. Thanks also to the
MMP-1 and MMP-3, at least in vitro (Refs 195, surgeons who have provided human tendon
198). Thus innervation, and the stimulation of specimens, including Mr Chris Constant, Mr
neuropeptide release by strain or friction at the Andrew Robinson, Mr Roger Hackney and Mr
tendon surface, is thought to be important for both Graham Holloway.
normal tendon function and tendinopathy,
affecting remodelling events in the tissue. Since References
peptide antagonists of substance P are already 1 Almekinders, L.C. and Temple, J.D. (1998)
available, having been used in clinical trials for Etiology, diagnosis, and treatment of tendonitis:
the treatment of pain, emesis and depression, it is an analysis of the literature. Med Sci Sports Exerc
possible that they could prove useful for the 30, 1183-1190, PubMed: 9710855
treatment of chronic tendinopathy. 2 Puddu, G., Ippolito, E. and Postacchini, F. (1976)
A classification of Achilles tendon disease. Am J
Concluding remarks Sports Med 4, 145-150, PubMed: 984291
Most tendinopathy is associated with degeneration, 3 Kannus, P. and Jozsa, L. (1991) Histopathological
which is thought to be an active, cell-mediated changes preceding spontaneous rupture of a
process involving increased turnover and tendon. A controlled study of 891 patients. J Bone
remodelling of the tendon ECM. There is a gradual Joint Surg Am 73, 1507-1525, PubMed: 1748700
transformation in the quantity and quality of the 4 Chard, M.D. et al. (1994) Rotator cuff
ECM that precedes tendon rupture. However, degeneration and lateral epicondylitis: a
some ECM turnover might be required to comparative histological study. Ann Rheum Dis
maintain the health of the tendon, particularly at 53, 30-34, PubMed: 8311552
sites exposed to high mechanical strain, such as 5 Astrom, M. and Rausing, A. (1995) Chronic
the shoulder and ankle. Degradation of the tendon Achilles tendinopathy. A survey of surgical and
ECM is mediated by a variety of metalloproteinase histopathologic findings. Clin Orthop 151-164,
15
expert reviews

PubMed: 7634699 19 Kannus, P. (2000) Structure of the tendon
6 Jarvinen, M. et al. (1997) Histopathological connective tissue. Scand J Med Sci Sports 10, 312-
findings in chronic tendon disorders. Scand J 320, PubMed: 11085557
Med Sci Sports 7, 86-95, PubMed: 9211609 20 Benjamin, M. (2004) The structure and function
7 Riley, G.P., Goddard, M.J. and Hazleman, B.L. of tendons. In Soft Tissue Rheumatology
(2001) Histopathological assessment and (Hazleman, B.L., Riley, G.P. and Speed, C.A.,
pathological significance of matrix degeneration eds), pp. 9-19, Oxford University Press, Oxford
in supraspinatus tendons. Rheumatology 21 Kastelic, J., Galeski, A. and Baer, E. (1978) The
(Oxford) 40, 229-230, PubMed: 11257166 multicomposite structure of tendon. Connect
8 Khan, K.M. et al. (2002) Time to abandon the Tissue Res 6, 11-23, PubMed: 149646
“tendinitis” myth. Bmj 324, 626-627, PubMed: 22 Cooper, R.R. and Misol, S. (1970) Tendon and
11895810 ligament insertion. A light and electron
9 Leadbetter, W.B. (1992) Cell-matrix response in microscopic study. J Bone Joint Surg Am 52, 1-20,
tendon injury. Clin Sports Med 11, 533-578, PubMed: 4189231
PubMed: 1638640 23 Benjamin, M., Evans, E.J. and Copp, L. (1986) The
10 Józsa, L. and Kannus, P. (1997) Overuse injuries histology of tendon attachments to bone in man.
of tendons. In Human Tendons: Anatomy, J Anat 149, 89-100, PubMed: 3693113
Physiology and Pathology (Józsa, L. and Kannus, 24 Evans, E.J., Benjamin, M. and Pemberton, D.J.
P., eds), pp. 164-253, Champaign, IL (1990) Fibrocartilage in the attachment zones of
11 Kannus, P. (1997) Etiology and pathophysiology the quadriceps tendon and patellar ligament of
of chronic tendon disorders in sports. Scand J man. J Anat 171, 155-162, PubMed: 2081702
Med Sci Sports 7, 107-112, PubMed: 9211611 25 Benjamin, M. et al. (1991) Quantitative
12 Fahlstrom, M., Lorentzon, R. and Alfredson, H. differences in the histology of the attachment
(2002) Painful conditions in the Achilles tendon zones of the meniscal horns in the knee joint of
region: a common problem in middle-aged man. J Anat 177, 127-134, PubMed: 1769887
competitive badminton players. Knee Surg 26 Schweitzer, R. et al. (2001) Analysis of the tendon
Sports Traumatol Arthrosc 10, 57-60, PubMed: cell fate using Scleraxis, a specific marker for
11819023 tendons and ligaments. Development 128, 3855-
13 Butler, D.L. et al. (1978) Biomechanics of 3866, PubMed: 11585810
ligaments and tendons. Exerc Sport Sci Rev 6, 27 Salingcarnboriboon, R. et al. (2003)
125-181, PubMed: 394967 Establishment of tendon-derived cell lines
14 Ker, R.F., Wang, X.T. and Pike, A.V. (2000) Fatigue exhibiting pluripotent mesenchymal stem cell-
quality of mammalian tendons. J Exp Biol 203 Pt like property. Exp Cell Res 287, 289-300, PubMed:
8, 1317-1327, PubMed: 10729280 12837285
15 Ker, R.F. (2002) The implications of the adaptable 28 Banes, A.J. et al. (1988) Cell populations of
fatigue quality of tendons for their construction, tendon: a simplified method for isolation of
repair and function. Comp Biochem Physiol A synovial cells and internal fibroblasts:
Mol Integr Physiol 133, 987-1000, PubMed: confirmation of origin and biologic properties. J
12485688 Orthop Res 6, 83-94, PubMed: 3334741
16 Oakes, B. (1994) Tendon-ligament basic science. 29 Gelberman, R.H. et al. (1986) Flexor tendon
In Oxford Textbook of Medicine (Harries, M. et repair. J Orthop Res 4, 119-128, PubMed: 3950804
al., eds), pp. 493-511, Oxford University Press, 30 Garner, W.L. et al. (1989) Identification of the
Oxford collagen-producing cells in healing flexor
17 Józsa, L. and Kannus, P. (1997) Functional and tendons. Plast Reconstr Surg 83, 875-879,
mechanical behaviour of tendons. In Human PubMed: 2652163
Tendons: Anatomy, Physiology and Pathology 31 Gelberman, R.H. et al. (1991) Fibroblast
(Józsa, L. and Kannus, P., eds), pp. 98-113, chemotaxis after tendon repair. J Hand Surg
Champaign, IL [Am] 16, 686-693, PubMed: 1880367
18 Józsa, L. and Kannus, P. (1997) Structure and 32 Khan, U., Edwards, J.C. and McGrouther, D.A.
metabolism of normal tendons. In Human (1996) Patterns of cellular activation after tendon
tendons: anatomy, physiology and pathology injury. J Hand Surg [Br] 21, 813-820, PubMed:
(Józsa, L.and Kannus, P., eds), pp. 46-95, 8982936
Champaign, IL, 33 Vogel, K.G. et al. (1986) Proteoglycan synthesis
16
expert reviews

by fibroblast cultures initiated from regions of molecular characteristics establishes a new clade
adult bovine tendon subjected to different within the vertebrate fibrillar collagen family. J
mechanical forces. Eur J Cell Biol 41, 102-112, Biol Chem 278, 31067-31077, PubMed: 12766169
PubMed: 3792332 47 Riley, G.P. et al. (1994) Tendon degeneration and
34 Koob, T.J. et al. (1992) Compression loading in chronic shoulder pain: changes in the collagen
vitro regulates proteoglycan synthesis by tendon composition of the human rotator cuff tendons in
fibrocartilage. Arch Biochem Biophys 298, 303- rotator cuff tendinitis. Ann Rheum Dis 53, 359-
312, PubMed: 1524441 366, PubMed: 8037494
35 Evanko, S.P. and Vogel, K.G. (1993) Proteoglycan 48 Duance, V.C. et al. (1977) The location of three
synthesis in fetal tendon is differentially collagen types in skeletal muscle. FEBS Lett 79,
regulated by cyclic compression in vitro. Arch 248-252, PubMed: 330230
Biochem Biophys 307, 153-164, PubMed: 7694546 49 Kumagai, J., Sarkar, K. and Uhthoff, H.K. (1994)
36 Vailas, A.C. et al. (1978) Physical activity and The collagen types in the attachment zone of
hypophysectomy on the aerobic capacity of rotator cuff tendons in the elderly: an
ligaments and tendons. J Appl Physiol 44, 542- immunohistochemical study. J Rheumatol 21,
546, PubMed: 205528 2096-2100, PubMed: 7869316
37 Robbins, J.R. and Vogel, K.G. (1994) Regional 50 Fukuta, S. et al. (1998) Identification of types II,
expression of mRNA for proteoglycans and IX and X collagens at the insertion site of the
collagen in tendon. Eur J Cell Biol 64, 264-270, bovine achilles tendon. Matrix Biol 17, 65-73,
PubMed: 7813514 PubMed: 9628253
38 Riley, G.P. et al. (2002) Matrix metalloproteinase 51 Sagarriga Visconti, C.S. et al. (1996) Biochemical
activities and their relationship with collagen analysis of collagens at the ligament-bone
remodelling in tendon pathology. Matrix Biol 21, interface reveals presence of cartilage-specific
185-195, PubMed: 11852234 collagens. Arch Biochem Biophys 135-142,
39 Brown, J.C. and Timpl, R. (1995) The collagen PubMed: 8638922
superfamily. Int Arch Allergy Immunol 107, 484- 52 Iozzo, R.V. and Murdoch, A.D. (1996)
490, PubMed: 7620364 Proteoglycans of the extracellular environment:
40 Aumailley, M. and Gayraud, B. (1998) Structure clues from the gene and protein side offer novel
and biological activity of the extracellular matrix. perspectives in molecular diversity and function.
J Mol Med 76, 253-265, PubMed: 9535559 Faseb J 10, 598-614, PubMed: 8621059
41 Prockop, D.J. and Kivirikko, K.I. (1995) 53 Iozzo, R.V. (1999) The biology of the small
Collagens: molecular biology, diseases, and leucine-rich proteoglycans. Functional network
potentials for therapy. Annu Rev Biochem 64, of interactive proteins. J Biol Chem 274, 18843-
403-434, PubMed: 7574488 18846, PubMed: 10383378
42 Myllyharju, J. and Kivirikko, K.I. (2001) 54 Scott, J.E. (1990) Proteoglycan:collagen
Collagens and collagen-related diseases. Ann interactions and subfibrillar structure in collagen
Med 33, 7-21, PubMed: 11310942 fibrils. Implications in the development and
43 Gelse, K., Poschl, E. and Aigner, T. (2003) ageing of connective tissues. J Anat 169, 23-35,
Collagens—structure, function, and biosynthesis. PubMed: 2384335
Adv Drug Deliv Rev 55, 1531-1546, PubMed: 55 Hardingham, T.E. and Fosang, A.J. (1992)
14623400 Proteoglycans: many forms and many functions.
44 Myllyharju, J. and Kivirikko, K.I. (2004) Faseb J 6, 861-870, PubMed: 1740236
Collagens, modifying enzymes and their 56 Iozzo, R.V. (1998) Matrix proteoglycans: from
mutations in humans, flies and worms. Trends molecular design to cellular function. Annu Rev
Genet 20, 33-43, PubMed: 14698617 Biochem 67, 609-652, PubMed: 9759499
45 Koch, M. et al. (2003) Collagen XXIV, a vertebrate 57 Vogel, K.G. and Heinegard, D. (1985)
fibrillar collagen with structural features of Characterization of proteoglycans from adult
invertebrate collagens: selective expression in bovine tendon. J Biol Chem 260, 9298-9306,
developing cornea and bone. J Biol Chem 278, PubMed: 4019475
43236-43244, PubMed: 12874293 58 Ameye, L. et al. (2002) Abnormal collagen fibrils
46 Boot-Handford, R.P. et al. (2003) A novel and in tendons of biglycan/fibromodulin-deficient
highly conserved collagen (pro(alpha)1(XXVII)) mice lead to gait impairment, ectopic
with a unique expression pattern and unusual ossification, and osteoarthritis. Faseb J 16, 673-
17
expert reviews

680, PubMed: 11978731 5 beta 1 and alpha v beta 3 integrins. J Biol Chem
59 Ameye, L. and Young, M.F. (2002) Mice deficient 278, 34605-34616, PubMed: 12807887
in small leucine-rich proteoglycans: novel in vivo 72 Dietz, H.C. et al. (1991) Marfan syndrome caused
models for osteoporosis, osteoarthritis, Ehlers- by a recurrent de novo missense mutation in the
Danlos syndrome, muscular dystrophy, and fibrillin gene. Nature 352, 337-339, PubMed:
corneal diseases. Glycobiology 12, 107R-116R, 1852208
PubMed: 12213783 73 Reinhardt, D.P. et al. (1996) Fibrillin-1 and
60 Scott, J.E., Orford, C.R. and Hughes, E.W. (1981) fibulin-2 interact and are colocalized in some
Proteoglycan-collagen arrangements in tissues. J Biol Chem 271, 19489-19496, PubMed:
developing rat tail tendon. An electron 8702639
microscopical and biochemical investigation. 74 Kassner, A. et al. (2003) Discrete integration of
Biochem J 195, 573-581, PubMed: 6459082 collagen XVI into tissue-specific collagen fibrils
61 Hedbom, E. and Heinegard, D. (1993) Binding of or beaded microfibrils. Matrix Biol 22, 131-143,
fibromodulin and decorin to separate sites on PubMed: 12782140
fibrillar collagens. J Biol Chem 268, 27307-27312, 75 Visconti, R.P. et al. (2003) Codistribution analysis
PubMed: 8262971 of elastin and related fibrillar proteins in early
62 Nakamura, N. et al. (2000) Decorin antisense vertebrate development. Matrix Biol 22, 109-121,
gene therapy improves functional healing of PubMed: 12782138
early rabbit ligament scar with enhanced 76 Timpl, R. et al. (2003) Fibulins: a versatile family
collagen fibrillogenesis in vivo. J Orthop Res 18, of extracellular matrix proteins. Nat Rev Mol Cell
517-523, PubMed: 11052486 Biol 4, 479-489, PubMed: 12778127
63 Wiberg, C. et al. (2002) Biglycan organizes 77 Ritty, T.M., Ditsios, K. and Starcher, B.C. (2002)
collagen VI into hexagonal-like networks Distribution of the elastic fiber and associated
resembling tissue structures. J Biol Chem 277, proteins in flexor tendon reflects function. Anat
49120-49126, PubMed: 12354766 Rec 268, 430-440, PubMed: 12420291
64 Ruoslahti, E. et al. (1992) Extracellular matrix/ 78 Labat-Robert, J., Bihari-Varga, M. and Robert, L.
growth factor interactions. Cold Spring Harb (1990) Extracellular matrix. FEBS Lett 268, 386-
Symp Quant Biol 57, 309-315, PubMed: 1339667 393, PubMed: 2166694
65 Hildebrand, A. et al. (1994) Interaction of the 79 Jozsa, L. et al. (1989) Fibronectin and laminin in
small interstitial proteoglycans biglycan, decorin Achilles tendon. Acta Orthop Scand 60, 469-471,
and fibromodulin with transforming growth PubMed: 2683566
factor beta. Biochem J 302 ( Pt 2), 527-534, 80 Lehto, M. et al. (1990) Fibronectin in the ruptured
PubMed: 8093006 human Achilles tendon and its paratenon. An
66 Schlessinger, J., Lax, I. and Lemmon, M. (1995) immunoperoxidase study. Ann Chir Gynaecol 79,
Regulation of growth factor activation by 72-77, PubMed: 2201247
proteoglycans: what is the role of the low affinity 81 Amiel, D. et al. (1991) Fibronectin in healing
receptors? Cell 83, 357-360, PubMed: 8521464 flexor tendons subjected to immobilization or
67 Hardingham, T.E. and Fosang, A.J. (1995) The early controlled passive motion. Matrix 11, 184-
structure of aggrecan and its turnover in 189, PubMed: 1870449
cartilage. J Rheumatol Suppl 43, 86-90, PubMed: 82 Chiquet, M. (1992) Tenascin: an extracellular
7752148 matrix protein involved in morphogenesis of
68 Margolis, R.U. and Margolis, R.K. (1994) epithelial organs. Kidney Int 41, 629-631,
Aggrecan-versican-neurocan family PubMed: 1374137
proteoglycans. Methods Enzymol 245, 105-126, 83 Gulcher, J.R. et al. (1991) Structure of the human
PubMed: 7539091 hexabrachion (tenascin) gene. Proc Natl Acad Sci
69 Elliott, D.H. (1965) Structure and Function of U S A 88, 9438-9442, PubMed: 1719530
Mammalian Tendon. Biol Rev Camb Philos Soc 84 Riley, G.P. et al. (1996) Tenascin-C and human
40, 392-421, PubMed: 14340913 tendon degeneration. Am J Pathol 149, 933-943,
70 Ramirez, F. and Pereira, L. (1999) The fibrillins. PubMed: 8780397
Int J Biochem Cell Biol 31, 255-259, PubMed: 85 Mackie, E.J., Halfter, W. and Liverani, D. (1988)
10216958 Induction of tenascin in healing wounds. J Cell
71 Bax, D.V. et al. (2003) Cell adhesion to fibrillin-1 Biol 107, 2757-2767, PubMed: 2462568
molecules and microfibrils is mediated by alpha 86 Whitby, D.J. and Ferguson, M.W. (1991) The
18
expert reviews

extracellular matrix of lip wounds in fetal, Achilles tendon. J Orthop Res 20, 1352-1357,
neonatal and adult mice. Development 112, 651- PubMed: 12472252
668, PubMed: 1724421 100 Goncalves-Neto, J. et al. (2002) Changes in
87 DiCesare, P. et al. (1994) Cartilage oligomeric collagen matrix composition in human posterior
matrix protein (COMP) is an abundant tibial tendon dysfunction. Joint Bone Spine 69,
component of tendon. FEBS Lett 354, 237-240, 189-194, PubMed: 12027311
PubMed: 7957930 101 Lapiere, C.M., Nusgens, B. and Pierard, G.E.
88 Oldberg, A. et al. (1992) COMP (cartilage (1977) Interaction between collagen type I and
oligomeric matrix protein) is structurally related type III in conditioning bundles organization.
to the thrombospondins. J Biol Chem 267, 22346- Connect Tissue Res 5, 21-29, PubMed: 141359
22350, PubMed: 1429587 102 Magnusson, S.P. et al. (2002) Collagen fibril size
89 Smith, R.K. et al. (1997) The distribution of and crimp morphology in ruptured and intact
cartilage oligomeric matrix protein (COMP) in Achilles tendons. Matrix Biol 21, 369-377,
tendon and its variation with tendon site, age PubMed: 12128074
and load. Matrix Biol 16, 255-271, PubMed: 103 Riley, G.P. et al. (1994) Glycosaminoglycans of
9501326 human rotator cuff tendons: changes with age
90 Briggs, M.D. et al. (1995) Pseudoachondroplasia and in chronic rotator cuff tendinitis. Ann Rheum
and multiple epiphyseal dysplasia due to Dis 53, 367-376, PubMed: 8037495
mutations in the cartilage oligomeric matrix 104 Birch, H.L., Bailey, A.J. and Goodship, A.E. (1998)
protein gene. Nat Genet 10, 330-336, PubMed: Macroscopic ‘degeneration’ of equine superficial
7670472 digital flexor tendon is accompanied by a change
91 Oldberg, A. et al. (1990) Structure and function of in extracellular matrix composition. Equine Vet J
extracellular matrix proteoglycans. Biochem Soc 30, 534-539, PubMed: 9844973
Trans 18, 789-792, PubMed: 2083676 105 Maffulli, N., Waterston, S.W. and Ewen, S.W.
92 Sage, E.H. and Bornstein, P. (1991) Extracellular (2002) Ruptured Achilles tendons show increased
proteins that modulate cell-matrix interactions. lectin stainability. Med Sci Sports Exerc 34, 1057-
SPARC, tenascin, and thrombospondin. J Biol 1064, PubMed: 12131241
Chem 266, 14831-14834, PubMed: 1714444 106 Tillander, B., Franzen, L. and Norlin, R. (2002)
93 Bornstein, P. (1992) Thrombospondins: structure Fibronectin, MMP-1 and histologic changes in
and regulation of expression. Faseb J 6, 3290- rotator cuff disease. J Orthop Res 20, 1358-1364,
3299, PubMed: 1426766 PubMed: 12472253
94 Miller, R.R. and McDevitt, C.A. (1991) 107 Ireland, D. et al. (2001) Multiple changes in gene
Thrombospondin in ligament, meniscus and expression in chronic human Achilles
intervertebral disc. Biochim Biophys Acta 1115, tendinopathy. Matrix Biol 20, 159-169, PubMed:
85-88, PubMed: 1958708 11420148
95 Tallon, C., Maffulli, N. and Ewen, S.W. (2001) 108 Alfredson, H. et al. (2003) cDNA-arrays and real-
Ruptured Achilles tendons are significantly more time quantitative PCR techniques in the
degenerated than tendinopathic tendons. Med investigation of chronic Achilles tendinosis. J
Sci Sports Exerc 33, 1983-1990, PubMed: 11740288 Orthop Res 21, 970-975, PubMed: 14554207
96 Chard, M.D., Gresham, A. and Hazleman, B.L. 109 Corps, A.N. et al. (2004) Versican splice variant
(1989) Age-related changes in the rotator cuff. Br messenger RNA expression in normal human
J Rheum 28, 19 (Abstract) Achilles tendon and tendinopathies.
97 Bank, R.A. et al. (1999) Lysylhydroxylation and Rheumatology (Oxford) 43, 969-972, PubMed:
non-reducible crosslinking of human 15138331
supraspinatus tendon collagen: changes with age 110 Alfredson, H. et al. (2001) In vivo microdialysis
and in chronic rotator cuff tendinitis. Ann Rheum and immunohistochemical analyses of tendon
Dis 58, 35-41, PubMed: 10343538 tissue demonstrated high amounts of free
98 Bailey, A.J. et al. (1975) Characterization of the glutamate and glutamate NMDAR1 receptors,
collagen of human hypertrophic and normal but no signs of inflammation, in Jumper’s knee. J
scars. Biochim Biophys Acta 405, 412-421, Orthop Res 19, 881-886, PubMed: 11562137
PubMed: 1180964 111 Everts, V. et al. (1996) Phagocytosis and
99 Eriksen, H.A. et al. (2002) Increased content of intracellular digestion of collagen, its role in
type III collagen at the rupture site of human turnover and remodelling. Histochem J 28, 229-
19
expert reviews

245, PubMed: 8762055 of joint contracture. Matrix 9, 200-205, PubMed:
112 Creemers, L.B. et al. (1998) Gelatinase A (MMP-2) 2550751
and cysteine proteinases are essential for the 127 Harper, J., Amiel, D. and Harper, E. (1992)
degradation of collagen in soft connective tissue. Inhibitors of collagenase in ligaments and
Matrix Biol 17, 35-46, PubMed: 9628251 tendons of rabbits immobilized for 4 weeks.
113 Matrisian, L.M. (1990) Metalloproteinases and Connect Tissue Res 28, 257-261, PubMed:
their inhibitors in matrix remodeling. Trends 1304441
Genet 6, 121-125, PubMed: 2132731 128 Amiel, D. et al. (1983) Stress deprivation effect on
114 Nagase, H. (1994) Matrix metalloproteinases. A metabolic turnover of the medial collateral
mini-review. Contrib Nephrol 107, 85-93, ligament collagen. A comparison between nine-
PubMed: 8004978 and 12-week immobilization. Clin Orthop 265-
115 Murphy, G. et al. (1994) Regulation of matrix 270, PubMed: 6821994
metalloproteinase activity. Ann N Y Acad Sci 732, 129 Akeson, W.H. et al. (1987) Effects of
31-41, PubMed: 7978800 immobilization on joints. Clin Orthop 28-37,
116 Cawston, T.E. (1995) Proteinases and inhibitors. PubMed: 3581580
Br Med Bull 51, 385-401, PubMed: 7552071 130 Majima, T. et al. (2000) In-vitro cyclic tensile
117 Birkedal-Hansen, H. (1995) Proteolytic loading of an immobilized and mobilized
remodeling of extracellular matrix. Curr Opin ligament autograft selectively inhibits mRNA
Cell Biol 7, 728-735, PubMed: 8573349 levels for collagenase (MMP-1). J Orthop Sci 5,
118 Clark, I.M. and Parker, A.E. (2003) 503-510, PubMed: 11180909
Metalloproteinases: their role in arthritis and 131 Arnoczky, S.P. et al. (2004) Ex vivo static tensile
potential as therapeutic targets. Expert Opin loading inhibits MMP-1 expression in rat tail
Ther Targets 7, 19-34, PubMed: 12556200 tendon cells through a cytoskeletally based
119 McCawley, L.J. and Matrisian, L.M. (2001) Matrix mechanotransduction mechanism. J Orthop Res
metalloproteinases: they’re not just for matrix 22, 328-333, PubMed: 15013092
anymore! Curr Opin Cell Biol 13, 534-540, 132 Arnoczky, S.P. et al. (2002) Activation of stress-
PubMed: 11544020 activated protein kinases (SAPK) in tendon cells
120 Lafleur, M.A., Handsley, M.M. and Edwards, following cyclic strain: the effects of strain
D.R. (2003) Metalloproteinases and their frequency, strain magnitude, and cytosolic
inhibitors in angiogenesis. Expert Rev Mol Med calcium. J Orthop Res 20, 947-952, PubMed:
2003, 1-39, PubMed: 14585170 12382958
121 Murphy, G. and Willenbrock, F. (1995) Tissue 133 Lavagnino, M. et al. (2003) Effect of amplitude
inhibitors of matrix metalloendopeptidases. and frequency of cyclic tensile strain on the
Methods Enzymol 248, 496-510, PubMed: 7674941 inhibition of MMP-1 mRNA expression in tendon
122 Vater, C.A., Mainardi, C.L. and Harris, E.D., Jr. cells: an in vitro study. Connect Tissue Res 44,
(1979) Inhibitor of human collagenase from 181-187, PubMed: 14504039
cultures of human tendon. J Biol Chem 254, 3045- 134 Cawston, T.E. et al. (1998) The role of oncostatin
3053, PubMed: 218961 M in animal and human connective tissue
123 Porat, S. et al. (1985) Increased collagenolytic collagen turnover and its localization within the
activity in severed and sutured tendons rheumatoid joint. Arthritis Rheum 41, 1760-1771,
following topical application of exogenous PubMed: 9778217
collagen in chickens. J Orthop Res 3, 43-48, 135 Archambault, J.M. et al. (2002) Rabbit tendon
PubMed: 2984391 cells produce MMP-3 in response to fluid flow
124 Piening, C. and Riederer-Henderson, M.A. (1989) without significant calcium transients. J Biomech
Neutral metalloprotease from tendons. J Orthop 35, 303-309, PubMed: 11858805
Res 7, 228-234, PubMed: 2537397 136 Archambault, J. et al. (2002) Stretch and
125 Harper, J., Amiel, D. and Harper, E. (1988) interleukin-1beta induce matrix
Collagenase production by rabbit ligaments and metalloproteinases in rabbit tendon cells in vitro.
tendon. Connect Tissue Res 17, 253-259, PubMed: J Orthop Res 20, 36-39, PubMed: 11853088
2850134 137 Archambault, J.M., Hart, D.A. and Herzog, W.
126 Harper, J., Amiel, D. and Harper, E. (1989) (2001) Response of rabbit Achilles tendon to
Collagenases from periarticular ligaments and chronic repetitive loading. Connect Tissue Res 42,
tendon: enzyme levels during the development 13-23, PubMed: 11696985
20
expert reviews

138 Koskinen, S.O. et al. (2004) Physical exercise can 149 Tortorella, M.D. et al. (1999) Purification and
influence local levels of matrix cloning of aggrecanase-1: a member of the
metalloproteinases and their inhibitors in ADAMTS family of proteins. Science 284, 1664-
tendon-related connective tissue. J Appl Physiol 1666, PubMed: 10356395
96, 861-864, PubMed: 14506093 150 Abbaszade, I. et al. (1999) Cloning and
139 Oshiro, W. et al. (2003) Flexor tendon healing in characterization of ADAMTS11, an aggrecanase
the rat: a histologic and gene expression study. J from the ADAMTS family. J Biol Chem 274,
Hand Surg [Am] 28, 814-823, PubMed: 14507513 23443-23450, PubMed: 10438522
140 Yoshihara, Y. et al. (2001) Biochemical markers in 151 Kuno, K. et al. (2000) ADAMTS-1 cleaves a
the synovial fluid of glenohumeral joints from cartilage proteoglycan, aggrecan. FEBS Lett 478,
patients with rotator cuff tear. J Orthop Res 19, 241-245, PubMed: 10930576
573-579, PubMed: 11518264 152 Somerville, R.P. et al. (2003) Characterization of
141 Gotoh, M. et al. (1997) Significance of granulation ADAMTS-9 and ADAMTS-20 as a distinct
tissue in torn supraspinatus insertions: an ADAMTS subfamily related to Caenorhabditis
immunohistochemical study with antibodies elegans GON-1. J Biol Chem 278, 9503-9513,
against interleukin-1 beta, cathepsin D, and PubMed: 12514189
matrix metalloprotease-1. J Orthop Res 15, 33-39, 153 Yamaji, N. et al. (2001) Novel metalloprotease
PubMed: 9066524 having aggrecanase activity. Patent WO0134785
142 Sandy, J.D. et al. (1991) Catabolism of aggrecan in 154 Collins-Racie, L.A. et al. (2004) ADAMTS-8
cartilage explants. Identification of a major exhibits aggrecanase activity and is expressed in
cleavage site within the interglobular domain. J human articular cartilage. Matrix Biol 23, 219-
Biol Chem 266, 8683-8685, PubMed: 2026585 230, PubMed: 15296936
143 Sandy, J.D. et al. (1992) The structure of aggrecan 155 Sandy, J.D. et al. (2001) Versican V1 proteolysis in
fragments in human synovial fluid. Evidence for human aorta in vivo occurs at the Glu441-Ala442
the involvement in osteoarthritis of a novel bond, a site that is cleaved by recombinant
proteinase which cleaves the Glu 373-Ala 374 ADAMTS-1 and ADAMTS-4. J Biol Chem 276,
bond of the interglobular domain. J Clin Invest 13372-13378, PubMed: 11278559
89, 1512-1516, PubMed: 1569188 156 Dickinson, S.C. et al. (2003) Cleavage of cartilage
144 Kaushal, G.P. and Shah, S.V. (2000) The new kids oligomeric matrix protein (thrombospondin-5)
on the block: ADAMTSs, potentially by matrix metalloproteinases and a disintegrin
multifunctional metalloproteinases of the ADAM and metalloproteinase with thrombospondin
family. J Clin Invest 105, 1335-1337, PubMed: motifs. Matrix Biol 22, 267-278, PubMed:
10811839 12853037
145 Cal, S. et al. (2002) Cloning, expression analysis, 157 Tortorella, M.D. et al. (2001) The role of ADAM-
and structural characterization of seven novel TS4 (aggrecanase-1) and ADAM-TS5
human ADAMTSs, a family of (aggrecanase-2) in a model of cartilage
metalloproteinases with disintegrin and degradation. Osteoarthritis Cartilage 9, 539-552,
thrombospondin-1 domains. Gene 283, 49-62, PubMed: 11520168
PubMed: 11867212 158 Caterson, B. et al. (1999) Mechanisms of
146 Colige, A. et al. (1999) Human Ehlers-Danlos proteoglycan metabolism that lead to cartilage
syndrome type VII C and bovine destruction in the pathogenesis of arthritis.
dermatosparaxis are caused by mutations in the Drugs Today (Barc) 35, 397-402, PubMed:
procollagen I N-proteinase gene. Am J Hum 12973442
Genet 65, 308-317, PubMed: 10417273 159 Vankemmelbeke, M.N. et al. (2001) Expression
147 Fernandes, R.J. et al. (2001) Procollagen II amino and activity of ADAMTS-5 in synovium. Eur J
propeptide processing by ADAMTS-3. Insights Biochem 268, 1259-1268, PubMed: 11231277
on dermatosparaxis. J Biol Chem 276, 31502- 160 Koshy, P.J. et al. (2002) The modulation of matrix
31509, PubMed: 11408482 metalloproteinase and ADAM gene expression in
148 Colige, A. et al. (2002) Cloning and human chondrocytes by interleukin-1 and
characterization of ADAMTS-14, a novel oncostatin M: a time-course study using real-
ADAMTS displaying high homology with time quantitative reverse transcription-
ADAMTS-2 and ADAMTS-3. J Biol Chem 277, polymerase chain reaction. Arthritis Rheum 46,
5756-5766, PubMed: 11741898 961-967, PubMed: 11953973
21
expert reviews

161 Tsuzaki, M. et al. (2003) IL-1 beta induces COX2, 173 Gotoh, M. et al. (2000) Perforation of rotator cuff
MMP-1, -3 and -13, ADAMTS-4, IL-1 beta and IL- increases interleukin 1beta production in the
6 in human tendon cells. J Orthop Res 21, 256- synovium of glenohumeral joint in rotator cuff
264, PubMed: 12568957 diseases. J Rheumatol 27, 2886-2892, PubMed:
162 Flannery, C.R. et al. (2002) Autocatalytic cleavage 11128681
of ADAMTS-4 (Aggrecanase-1) reveals multiple 174 Gotoh, M. et al. (2001) Interleukin-1-induced
glycosaminoglycan-binding sites. J Biol Chem subacromial synovitis and shoulder pain in
277, 42775-42780, PubMed: 12202483 rotator cuff diseases. Rheumatology (Oxford) 40,
163 Kashiwagi, M. et al. (2004) Altered proteolytic 995-1001, PubMed: 11561109
activities of ADAMTS-4 expressed by C-terminal 175 Fu, S.C. et al. (2002) Increased expression of
processing. J Biol Chem 279, 10109-10119, transforming growth factor-beta1 in patellar
PubMed: 14662755 tendinosis. Clin Orthop 174-183, PubMed:
164 Wang, P. et al. (2004) Proprotein convertase furin 12072760
interacts with and cleaves pro-ADAMTS4 176 Hosaka, Y. et al. (2002) Localization of cytokines
(Aggrecanase-1) in the trans-Golgi network. J in tendinocytes of the superficial digital flexor
Biol Chem 279, 15434-15440, PubMed: 14744861 tendon in the horse. J Vet Med Sci 64, 945-947,
165 Gao, G. et al. (2004) ADAMTS4 (aggrecanase-1) PubMed: 12419874
activation on the cell surface involves C-terminal 177 Kjaer, M. et al. (2000) In vivo studies of
cleavage by glycosylphosphatidyl inositol- peritendinous tissue in exercise. Scand J Med Sci
anchored membrane type 4-matrix Sports 10, 326-331, PubMed: 11085559
metalloproteinase and binding of the activated 178 Langberg, H. et al. (2002) Exercise-induced
proteinase to chondroitin sulfate and heparan increase in interstitial bradykinin and adenosine
sulfate on syndecan-1. J Biol Chem 279, 10042- concentrations in skeletal muscle and
10051, PubMed: 14701864 peritendinous tissue in humans. J Physiol 542,
166 Kashiwagi, M. et al. (2001) TIMP-3 is a potent 977-983, PubMed: 12154194
inhibitor of aggrecanase 1 (ADAM-TS4) and 179 Langberg, H. et al. (2002) Substantial elevation of
aggrecanase 2 (ADAM-TS5). J Biol Chem 276, interleukin-6 concentration in peritendinous
12501-12504, PubMed: 11278243 tissue, in contrast to muscle, following prolonged
167 Rees, S.G. et al. (2000) Catabolism of aggrecan, exercise in humans. J Physiol 542, 985-990,
decorin and biglycan in tendon. Biochem J 350 Pt PubMed: 12154195
1, 181-188, PubMed: 10926842 180 Tsuzaki, M. et al. (2003) ATP modulates load-
168 Samiric, T., Ilic, M.Z. and Handley, C.J. (2004) inducible IL-1beta, COX 2, and MMP-3 gene
Characterisation of proteoglycans and their expression in human tendon cells. J Cell Biochem
catabolic products in tendon and explant cultures 89, 556-562, PubMed: 12761889
of tendon. Matrix Biol 23, 127-140, PubMed: 181 Wang, J.H. et al. (2003) Cyclic mechanical
15246111 stretching of human tendon fibroblasts increases
169 Samiric, T., Ilic, M.Z. and Handley, C.J. (2004) the production of prostaglandin E2 and levels of
Large aggregating and small leucine-rich cyclooxygenase expression: a novel in vitro
proteoglycans are degraded by different model study. Connect Tissue Res 44, 128-133,
pathways and at different rates in tendon. Eur J PubMed: 14504032
Biochem 271, 3612-3620, PubMed: 15317597 182 Wang, J.H. et al. (2004) Repetitively stretched
170 Attur, M.G. et al. (2002) Osteoarthritis or tendon fibroblasts produce inflammatory
osteoarthrosis: the definition of inflammation mediators. Clin Orthop 243-250, PubMed:
becomes a semantic issue in the genomic era of 15187863
molecular medicine. Osteoarthritis Cartilage 10, 183 Li, Z. et al. (2004) Inflammatory response of
1-4, PubMed: 11795977 human tendon fibroblasts to cyclic mechanical
171 Abramson, S.P. et al. (2001) Nitric oxide and stretching. Am J Sports Med 32, 435-440,
inflammatory mediators in the perpetuation of PubMed: 14977670
osteoarthritis. Curr Rheumatol Rep 3, 535-541, 184 Alfredson, H., Thorsen, K. and Lorentzon, R.
PubMed: 11709117 (1999) In situ microdialysis in tendon tissue: high
172 Amin, A.R. et al. (2000) COX-2, NO, and cartilage levels of glutamate, but not prostaglandin E2 in
damage and repair. Curr Rheumatol Rep 2, chronic Achilles tendon pain. Knee Surg Sports
447-453, PubMed: 11123096 Traumatol Arthrosc 7, 378-381, PubMed:
22
expert reviews

10639657 glutamate in tennis elbow. Acta Orthop Scand 71,
185 Alfredson, H. and Lorentzon, R. (2002) Chronic 475-479, PubMed: 11186404
tendon pain: no signs of chemical inflammation 193 Alfredson, H. et al. (2001) Glutamate NMDAR1
but high concentrations of the neurotransmitter receptors localised to nerves in human Achilles
glutamate. Implications for treatment? Curr tendons. Implications for treatment? Knee Surg
Drug Targets 3, 43-54, PubMed: 11899264 Sports Traumatol Arthrosc 9, 123-126, PubMed:
186 Cawston, T.E. and Rowan, A. (1998) Prevention 11354854
of cartilage breakdown by matrix 194 Gotoh, M. et al. (1998) Increased substance P in
metalloproteinase inhibition—a realistic subacromial bursa and shoulder pain in rotator
therapeutic target? Br J Rheumatol 37, 353-356, cuff diseases. J Orthop Res 16, 618-621, PubMed:
PubMed: 9619881 9820287
187 Whittaker, M. et al. (1999) Design and 195 Hart, D.A., Kydd, A. and Reno, C. (1999) Gender
therapeutic application of matrix and pregnancy affect neuropeptide responses of
metalloproteinase inhibitors. Chem Rev 99, 2735- the rabbit Achilles tendon. Clin Orthop 237-246,
2776, PubMed: 11749499 PubMed: 10627708
188 Drummond, A.H. et al. (1999) Preclinical and 196 Hart, D.A. et al. (1998) Gender and neurogenic
clinical studies of MMP inhibitors in cancer. Ann variables in tendon biology and repetitive
N Y Acad Sci 878, 228-235, PubMed: 10415734 motion disorders. Clin Orthop 44-56, PubMed:
189 Brown, M.F. et al. (1997) Sensory and 9646746
sympathetic innervation of the vertebral 197 Hart, D.A., Frank, C.B. and R.C., B. (1995)
endplate in patients with degenerative disc Inflammatory processes in repetitive motion and
disease. J Bone Joint Surg Br 79, 147-153, overuse syndromes:potential role of neurogenic
PubMed: 9020464 mechanisms in tendons and ligaments. In
190 Freemont, A.J. et al. (1997) Nerve ingrowth into Repetitive Motion Disorders of the Upper
diseased intervertebral disc in chronic back pain. Extremity (Gordon, S.L., Blair, S.J. and Fine, L.J.,
Lancet 350, 178-181, PubMed: 9250186 eds), pp. 247-262, American Academy of
191 Sanchis-Alfonso, V., Rosello-Sastre, E. and Orthopaedic Surgeons, Rosemont, IL
Subias-Lopez, A. (2001) Neuroanatomic basis for 198 Hart, D.A. and Reno, C. (1998) Pregnancy alters
pain in patellar tendinosis (“jumper’s knee”): a the in vitro responsiveness of the rabbit medial
neuroimmunohistochemical study. Am J Knee collateral ligament to neuropeptides: effect on
Surg 14, 174-177, PubMed: 11491428 mRNA levels for growth factors, cytokines,
192 Alfredson, H. et al. (2000) In vivo investigation of iNOS, COX-2, metalloproteinases and TIMPs.
ECRB tendons with microdialysis technique—no Biochim Biophys Acta 1408, 35-43, PubMed:
signs of inflammation but high amounts of 9784599
23
expert reviews

Further reading, resources and contacts
Tendon structure and function
Kannus, P. (2000) Structure of the tendon connective tissue. Scand J Med Sci Sports 10, 312-320, PubMed:
11085557
Benjamin, M. (2004) The structure and function of tendons. In Soft Tissue Rheumatology (Hazleman, B.L.,
Riley, G.P. and Speed, C.A., eds), pp. 9-19, Oxford University Press, Oxford
Oakes, B. (1994) Tendon-ligament basic science. In Oxford Textbook of Medicine (Harries, M. et al., eds),
pp. 493-511, Oxford University Press, Oxford
Tendon pathology
Kannus, P. (1997) Etiology and pathophysiology of chronic tendon disorders in sports. Scand J Med Sci
Sports 7, 78-85, PubMed: 9211608
Józsa, L. and Kannus, P. (1997) Overuse injuries of tendons. In Human Tendons: Anatomy, Physiology and
Pathology (Józsa, L. and Kannus, P., eds), pp. 164-253, Champaign, IL
Riley, G. (2004) The pathogenesis of tendinopathy. A molecular perspective. Rheumatology (Oxford) 43,
131-142, PubMed: 12867575
Riley, G.P. (2004) Tendon and ligament biochemistry and pathology. In Soft Tissue Rheumatology
(Hazleman, B.L., Riley, G.P. and Speed, C.A., eds), pp. 20-53, Oxford University Press, Oxford
Leadbetter, W.B. (1992) Cell-matrix response in tendon injury. Clin Sports Med 11, 533-578, PubMed:
1638640
Treatment of tendinopathy
Almekinders, L.C. and Temple, J.D. (1998) Etiology, diagnosis, and treatment of tendonitis: an analysis of
the literature. Med Sci Sports Exerc 30, 1183-1190, PubMed: 9710855
el Hawary, R., Stanish, W.D. and Curwin, S.L. (1997) Rehabilitation of tendon injuries in sport. Sports Med
24, 347-358, PubMed: 9368280
Collagen
Myllyharju, J. and Kivirikko, K.I. (2004) Collagens, modifying enzymes and their mutations in humans, flies
and worms. Trends Genet 20, 33-43, PubMed: 14698617
Proteoglycan
Iozzo, R.V. (1998) Matrix proteoglycans: from molecular design to cellular function. Annu Rev Biochem 67,
609-652, PubMed: 9759499
Extracellular matrix in general

Aumailley, M. and Gayraud, B. (1998) Structure and biological activity of the extracellular matrix. J Mol Med
76, 253-265, PubMed: 9535559
Matrix metalloproteinases
Clark, I.M. and Parker, A.E. (2003) Metalloproteinases: their role in arthritis and potential as therapeutic
targets. Expert Opin Ther Targets 7, 19-34, PubMed: 12556200
McCawley, L.J. and Matrisian, L.M. (2001) Matrix metalloproteinases: they’re not just for matrix anymore!
Curr Opin Cell Biol 13, 534-540, PubMed: 11544020
Aggrecanases
Apte, S.S. (2004) A disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motifs:
the ADAMTS family. Int J Biochem Cell Biol 36, 981-985, PubMed: 15094112
Recent related article in Expert Reviews in Molecular Medicine:

Lafleur, M.A., Handsley, M.M. and Edwards, D.R. (2003) Metalloproteinases and their inhibitors in
angiogenesis. Expert Rev Mol Med 5(23), 1-39, PubMed: 14585170
24
expert reviews

Features associated with this article
Figures
Figure 1. Structure of tendon.
Figure 2. Synthesis of a fibril-forming collagen.
Figure 3. Proteoglycans in tendon.
Figure 4. Histopathology of tendinopathy.
Figure 5. Domain structure of matrix metalloproteinases (MMPs) and ADAMTS.
Table
Table 1. Molecular composition of tendon extracellular matrix.
Table 2. Major known or putative substrates of the matrix metalloproteinases.
Citation details for this article

Graham Riley (2005) Chronic tendon pathology: molecular basis and therapeutic implications. Expert Rev.
Mol. Med. Vol. 7, Issue 5, 24 March, DOI: 10.1017/S1462399405008963
25

Chronic Tendon Pathology: Molecular Basis and Therapeutic Implications

Uploaded by

Copyright:

Available Formats

Chronic Tendon Pathology: Molecular Basis and Therapeutic Implications

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Chronic Tendon Pathology: Molecular Basis and Therapeutic Implications

Uploaded by

Copyright:

Available Formats

http://www.expertreviews.

Chronic tendon pathology: molecular basis

Institute URL: http://www.addenbrookes.org.uk

Chronic tendon pathology: molecular basis

Chronic tendon pathology: molecular basis

Table 1. Molecular composition of tendon extracellular matrix

Chronic tendon pathology: molecular basis

Chronic tendon pathology: molecular basis

c Cleavage of propeptides carry one to four chains of GAG, which can be

Chronic tendon pathology: molecular basis

Chronic tendon pathology: molecular basis

Chronic tendon pathology: molecular basis

Chronic tendon pathology: molecular basis

Chronic tendon pathology: molecular basis

Collagenases MMP-1 Interstitial collagenase 1 Fibrillar collagens types I, II, III

Gelatinases MMP-2 Gelatinase A, 72 kDa gelatinase Nonfibrillar collagens, gelatin

Stromelysins MMP-3 Stromelysin 1, transin Proteoglycans, fibronectin, laminin,

Matrilysins MMP-7 Matrilysin, PUMP-1 Proteoglycans, link protein, fibronectin,

Elastase MMP-12 Macrophage elastase, Elastin, nonfibrillar collagens

Transmembrane MMP-14 MT1-MMP Pro-MMP-2, (MMP-13), gelatin, tenascin,

GPI anchored MMP-17 MT4-MMP Pro-MMP-2, gelatin

Miscellaneous MMP-11 Stromelysin-3 α1-Proteinase inhibitor, IGFBP-1

Chronic tendon pathology: molecular basis

Gelatinases: MMP-2, MMP-9 Zn2+

Disintegrin-like Cys-rich TS repeats

Domain structure of matrix metalloproteinases (MMPs) and ADAMTS

MMPs in tendon implicated in the remodelling of tendon that

Chronic tendon pathology: molecular basis

Chronic tendon pathology: molecular basis

Chronic tendon pathology: molecular basis

Chronic tendon pathology: molecular basis

Chronic tendon pathology: molecular basis

Chronic tendon pathology: molecular basis

Chronic tendon pathology: molecular basis

Chronic tendon pathology: molecular basis

Chronic tendon pathology: molecular basis

Chronic tendon pathology: molecular basis

Chronic tendon pathology: molecular basis

Chronic tendon pathology: molecular basis

Chronic tendon pathology: molecular basis

Extracellular matrix in general

Recent related article in Expert Reviews in Molecular Medicine:

Chronic tendon pathology: molecular basis

Citation details for this article

You might also like