Is cartilage sGAG content related to early changes in cartilage disease? Implications for interpretation of dGEMRIC.

OBJECTIVE: This study investigates sulphated glycosaminoglycans (sGAG) content changes in early osteoarthritis (OA), and whether contrast-enhanced magnetic resonance imaging (MRI) of cartilage in vitro may identify early event of OA pathology. METHOD: Osteochondral plugs from patients with hip OA or femoral neck fracture (reference group) were collected and analysed by 1.5 T MRI with ΔR1 as a measure of cartilage contrast concentration. Cartilage hydration, contents of sGAG, cartilage oligomeric matrix protein (COMP), hydroxyproline, denatured collagen, and aggrecan TEGE(392) neoepitope were determined and histological grading was performed. RESULTS: sGAG content correlated to ΔR1, although no difference in either of these parameters was detectable between OA and reference cartilage at 4 h of contrast equilibration. In contrast, biochemical analysis of other cartilage matrix constituents showed distinct alterations typical for early cartilage degradation in OA cartilage and with clear evidence for increased aggrecan turnover. CONCLUSION: In the present in vitro study, cartilage sGAG content could not distinguish between early OA cartilage and reference cartilage. Given, that delayed gadolinium enhanced MRI of cartilage (dGEMRIC) indicates early events in the pathogenesis of OA in vivo, our results from the in vitro studies imply other, additional factors than cartilage sGAG content, e.g., alterations in diffusion or increased supply of contrast agent in the diseased joint. Alternatively, an altered dGEMRIC reflects later stages of OA, when sGAG content decreases. Further investigations are warranted, to understand variations in sGAG content in pathology, an essential background for interpreting dGEMRIC measurements.

Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) is a chronic and slowly progressive disease for which biomarkers may be able to provide a more rapid indication of therapeutic responses to therapy than is currently available; this could accelerate and facilitate OA drug discovery and development programs. The goal of this document is to provide a summary and guide to the application of in vitro (biochemical and other soluble) biomarkers in the development of drugs for OA and to outline and stimulate a research agenda that will further this goal. METHODS: The Biomarkers Working Group representing experts in the field of OA biomarker research from both academia and industry developed this consensus document between 2007 and 2009 at the behest of the Osteoarthritis Research Society International Federal Drug Administration initiative (OARSI FDA initiative). RESULTS: This document summarizes definitions and classification systems for biomarkers, the current outcome measures used in OA clinical trials, applications and potential utility of biomarkers for development of OA therapeutics, the current state of qualification of OA-related biomarkers, pathways for biomarker qualification, critical needs to advance the use of biomarkers for drug development, recommendations regarding practices and clinical trials, and a research agenda to advance the science of OA-related biomarkers. CONCLUSIONS: Although many OA-related biomarkers are currently available they exist in various states of qualification and validation. The biomarkers that are likely to have the earliest beneficial impact on clinical trials fall into two general categories, those that will allow targeting of subjects most likely to either respond and/or progress (prognostic value) within a reasonable and manageable time frame for a clinical study (for instance within 1-2 years for an OA trial), and those that provide early feedback for preclinical decision-making and for trial organizers that a drug is having the desired biochemical effect. As in vitro biomarkers are increasingly investigated in the context of specific drug treatments, advances in the field can be expected that will lead to rapid expansion of the list of available biomarkers with increasing understanding of the molecular processes that they represent.

Ultrastructural immunolocalization of cartilage oligomeric matrix protein (COMP) in the articular cartilage on the equine third carpal bone in trained and untrained horses.

The present study was designed to delineate the presence of COMP at the ultrastructural level comparing concentrations between two areas of articular cartilage from the equine third carpal bone, subjected to different loading, from trained and untrained horses. We also analyzed the fibril thickness of collagen type II in the same compartments and zones. Samples were collected from high load-bearing areas of the dorsal radial facet (intermittent high load) and an area of the palmar condyle (low constant load) in five non-trained and three trained young racehorses. The data show that COMP is much less abundant in the matrix in intermittent high loaded areas of articular cartilage from trained horses as compared to the untrained horses (p=0.036). On the other hand, the untrained horses often displayed a higher immunolabeling in loaded areas compared to unloaded areas, indicating that an adequate dynamic load promotes COMP synthesis and/or retention, while an excessive load may have an opposite effect. The collagen fibril diameter showed marked variation between individuals. The present study indicates that dynamic in vivo compression at high load and frequency lowers matrix content of COMP in the articular cartilage of the third carpal bone. It also indicates that the collagen network is influenced by mechanical load following by strenuous exercise.

Glucosamine but not ibuprofen alters cartilage turnover in osteoarthritis patients in response to physical training.

OBJECTIVE: To investigate changes in levels of serum cartilage oligomeric matrix protein (COMP) and urine c-telopeptide of type-2 collagen (CTX-II) as markers for cartilage turnover in patients with osteoarthritis (OA) of the knee, in response to muscle strength training in combination with treatment with glucosamine, ibuprofen or placebo. DESIGN: A 12-week double blind, placebo controlled, randomized study. METHOD: Thirty-six elderly patients with bilateral tibiofemoral knee OA determined by radiography were randomly assigned to treatment with glucosamine (n=12), ibuprofen (n=12) or placebo (n=12) during 12 weeks of strength training of both legs with focus on the quadriceps muscle. Strength tests (5 repetition maximum), blood and urine sampling were performed before and after the training period. Serum COMP and urinary CTX-II were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: All three groups increased their muscle strength following 12 weeks of strength training (P<0.001). Serum COMP levels were reduced in the glucosamine-treated group after the training period (P=0.012), whereas they did not change in the two other groups. Glucosamine reduced COMP statistically significant compared to both placebo and ibuprofen; the mean reduction with glucosamine was 13% vs placebo (P=0.0378) and 17% vs ibuprofen (P=0.0122). Urinary CTX-II levels did not change significantly in any of the three experimental groups. CONCLUSION: Serum COMP decreased significantly over the 12-week training period when treatment with glucosamine was added to the training regimen. This suggests an effect by glucosamine on the response of the OA cartilage to a period of joint loading in humans with knee OA.

Interactions of histidine-rich glycoprotein with immunoglobulins and proteins of the complement system.

This study describes how the serum protein histidine-rich glycoprotein (HRG) affects the complement system. We show that HRG binds strongly to several complement proteins: C1q, factor H and C4b-binding protein and that it is found complexed with these proteins in human sera and synovial fluids of rheumatoid arthritis patients. HRG also binds C8 and to a lesser extent mannose-binding lectin, C4 and C3. However, HRG alone neither activates nor inhibits complement. Both HRG and C1q bind to necrotic cells and increase their phagocytosis. We found that C1q competes weakly with HRG for binding to necrotic cells whilst HRG does not compete with C1q. Furthermore, HRG enhances complement activation on necrotic cells measured as deposition of C3b. We show that HRG inhibits the formation of immune complexes of ovalbumin/anti-ovalbumin, whilst the reverse holds for C1q. Immune complexes formed in the presence of HRG show enhanced complement activation, whilst those formed in the presence of C1q show diminished complement activation. Taken together, HRG may assist in the maintenance of normal immune function by mediating the clearance of necrotic material, inhibiting the formation of insoluble immune complexes and enhancing their ability to activate complement, resulting in faster clearance.

COMP: a candidate molecule in the pathogenesis of systemic sclerosis with a potential as a disease marker.

OBJECTIVE: Cartilage oligomeric matrix protein (COMP), primarily found in cartilage, is thought to be an important regulator of assembly and maintenance of the fibrillar collagen I and II networks. Recently, COMP was shown to be produced by skin fibroblasts from patients with systemic sclerosis (SSc, or scleroderma). The purpose of this study was to examine whether COMP is released from skin to serum in patients with SSc, and may serve as indicator of activity of skin involvement. METHODS: Serum COMP levels were measured by enzyme linked immunosorbent assay in patients with SSc whose skin involvement was assessed with the modified Rodnan skin score (mRss) and high frequency ultrasound. The presence of COMP in skin biopsies was assessed by Western blot using a monoclonal antibody specific for the very C-terminal end of human COMP. RESULTS: Serum COMP correlated to skin involvement as measured by the mRss (n = 70; r(S) = 0.60; p<0.001), to skin thickness measured by ultrasound (n = 88; r(S) = 0.55; p<0.001) and inversely to skin echogenicity measured by ultrasound (n = 88; r(S) = -0.40; p<0.001). In 70 patients followed longitudinally there was a correlation between changes in serum COMP (n = 307) and changes in mRss (r(S) = 0.35; p = 0.008). In individual patients monitored with repeated measurements, serum COMP changes closely paralleled changes in mRss. A C-terminal COMP fragment, with an apparent molecular mass of 56 kDa, was identified in SSc skin biopsies, while no COMP reactivity was detected in normal skin. CONCLUSION: The high turnover of COMP in SSc skin suggests a pathophysiological role. Serum COMP shows promise as a new biomarker in SSc.

Giant-cell tumour of the knee: the condition of the cartilage after treatment by curettage and cementing.

We reviewed nine patients at a mean period of 11 years (6 to 16) after curettage and cementing of a giant-cell tumour around the knee to determine if there were any long-term adverse effects on the cartilage. Plain radiography, MRI, delayed gadolinium-enhanced MRI of the cartilage and measurement of the serum level of cartilage oligomeric matrix protein were carried out. The functional outcome was evaluated using the Lysholm knee score. Each patient was physically active and had returned to their previous occupation. Most participated in recreational sports or exercise. The mean Lysholm knee score was 92 (83 to 100). Only one patient was found to have cartilage damage adjacent to the cement. This patient had a history of intra-articular fracture and local recurrence, leading to degenerative changes. Interpretation of the data obtained from delayed gadolinium-enhanced MRI of the cartilage was difficult, with variation in the T1 values which did not correlate with the clinical or radiological findings. We did not find it helpful in the early diagnosis of degeneration of cartilage. We also found no obvious correlation between the serum cartilage oligomeric matrix protein level and the radiological and MR findings, function, time after surgery and the age of the patient. In summary, we found no evidence that the long-term presence of cement close to the knee joint was associated with the development of degenerative osteoarthritis.

Altered homeostasis of extracellular matrix proteins in joints of standardbred trotters during a long-term training programme.

This study evaluates how strenuous training, age and lameness influence the release of cartilage oligomeric matrix protein (sf-COMP), aggrecan and collagen type II into synovial fluid in 28 (19.5-40 months) Standardbred trotters (STB), during a long-term training programme (24 months). All the horses were trained by the same trainer and were healthy on entering the training programme. Synovial fluid (sf) from the left middle carpal joint in each subject was sampled every third month. Enzyme-linked immunosorbent assay was used to determine the concentrations of sf-COMP, sf-aggrecan and sf-collagen type II. Concentration of sf-COMP decreased with increasing age and total days of training. The concentration of sf-COMP was found similarly related to both age and total days of training, so they could not be differentiated. It was also shown that the concentration of collagen type II degradation products increased with total days of training. The study shows that extensive and long-term training programme induces metabolic changes in articular cartilage exemplified by reduced release and synthesis of COMP. This is most likely due to strenuous training leading to inappropriate load on the articular cartilage.

Diurnal variation in serum levels of cartilage oligomeric matrix protein in patients with knee osteoarthritis or rheumatoid arthritis.

OBJECTIVE: To monitor changes in serum concentrations of cartilage oligomeric matrix protein (COMP) during a 24-h period to determine any diurnal variation, and to estimate the half life of COMP in the circulation in patients with symptomatic knee osteoarthritis and in those with rheumatoid arthritis. METHODS: Serum samples were drawn every 4 h (7 samples/patient over 24 h) in 10 patients with knee osteoarthritis and 14 patients with rheumatoid arthritis. Osteoarthritis was defined radiographically and clinically (American College of Rheumatology (ACR) criteria) and rheumatoid arthritis according to the 1987 ACR criteria. Serum COMP was measured by sandwich ELISA. A statistical model for the diurnal variation in the COMP levels was developed using the computer program NONMEM. RESULTS: No considerable changes in COMP levels were observed during the day between 08:00 and 21:00 in either group. A significant decrease in serum COMP was apparent during bed rest at night, reaching the lowest levels between 04:00 and 05:00 (p<0.03 or better v all other time points) in patients with osteoarthritis and in those with rheumatoid arthritis. From the rate of decreasing serum COMP levels, a putative half life of COMP in the circulation was estimated to be 7.4 h. CONCLUSION: During normal daytime activities, serum COMP levels are constant. The decrease during the night indicates a rapid elimination of COMP once it has reached the circulation. The stable COMP levels during the day suggest that it is not necessary to further standardise the time of serum sampling in clinical practice.

Classification of osteoarthritis biomarkers: a proposed approach.

OBJECTIVE: Osteoarthritis (OA) biomarkers are needed by researchers and clinicians to assist in disease diagnosis and assessment of disease severity, risk of onset, and progression. As effective agents for OA are developed and tested in clinical studies, biomarkers that reliably mirror or predict the progression or amelioration of OA will also be needed. METHODS: The NIH-funded OA Biomarkers Network is a multidisciplinary group interested in the development and validation of OA biomarkers. This review summarizes our efforts to characterize and classify OA biomarkers. RESULTS: We propose the "BIPED" biomarker classification (which stands for Burden of Disease, Investigative, Prognostic, Efficacy of Intervention and Diagnostic), and offer suggestions on optimal study design and analytic methods for use in OA investigations. CONCLUSION: The BIPED classification provides specific biomarker definitions with the goal of improving our ability to develop and analyze OA biomarkers, and to communicate these advances within a common framework.

Ultrastructural immunolocalisation of bone sialoprotein in the osteocartilagenous interface of the equine third carpal bone.

REASONS FOR PERFORMING STUDY: One of the most common causes of lameness in racehorses is osteoarthritis (OA). Pathogenesis is not clear and pathological processes of the different joint tissues interact in often progressive events. The interface between cartilage and newly synthesised bone has been shown to be particularly enriched in bone sialoprotein (BSP), a cell-binding matrix protein. OBJECTIVES: To establish whether changes in the concentration of BSP may serve as a marker for early biochemical changes of the subchondral bone. METHODS: Articular cartilage, cartilage/bone interface and subchondral bone of the proximal third carpal bone from 3 Standardbred trotters were analysed ultrastructurally for the presence of BSP in normal and degenerative areas. RESULTS: A marked increase of BSP in the cartilage/bone interface with degenerative changes of the bone and cartilage compared to the morphologically intact cartilage/bone interface was noted, but levels of the protein were distinctly lower in the distal bone. CONCLUSIONS: The results indicate that BSP has the potential to be used as a marker for changes in bone metabolism in the subchondral bone. POTENTIAL RELEVANCE: Tools to monitor early biochemical changes within the connective tissues of the joint in vivo are essential in studies of the pathogenesis of OA. These could be used to monitor and understand such changes in relation to load, exercise, training programmes, inflammation and the development of OA.

Prognostic laboratory markers of joint damage in rheumatoid arthritis.

OBJECTIVE: To investigate whether determination of a set of laboratory markers at baseline provides prognostic information on joint damage in hands and feet in rheumatoid arthritis. METHODS: 183 patients with early rheumatoid arthritis included in a prospective study were examined. Radiographic changes in hands and feet at 5 and 10 years after inclusion were evaluated (Larsen). The markers analysed were: erythrocyte sedimentation rate (ESR); HLA-DRB alleles typed by restriction fragment length polymorphism; and C reactive protein, cartilage oligomeric matrix protein (COMP), rheumatoid factor (RF) (IgG, IgA, and IgM subtypes), antibodies against cyclic citrullinated peptide (anti-CCP), and antibodies against interleukin 1alpha (anti-IL1alpha), analysed by immunoassays. Multiple linear regression with backward elimination was used to determine the prognostic value of the variables. RESULTS: 117/176 patients were positive for IgG RF, 138/176 for IgA RF, 139/176 for IgM RF, 140/176 for anti-CCP, and 40/182 for anti-IL1alpha. After five years, ESR, the presence of IgA RF, serum COMP, and the presence of anti-CCP were significantly associated with more severe joint damage, and the presence of anti-IL1alpha with less severe joint damage. Baseline C reactive protein and anti-CCP predicted radiographic outcome after 10 years. A stronger prediction was obtained by combining the prognostic factors. CONCLUSIONS: Early determination of anti-CCP, IgA RF, anti-IL-1alpha, ESR, C reactive protein, and COMP predicted the development of joint damage in hands and feet in this cohort. A combination of these measures reflecting different aspects of the disease process should be useful for evaluating prognosis in individual patients with early rheumatoid arthritis.

Enhanced concentration of COMP (cartilage oligomeric matrix protein) in osteochondral fractures from racing Thoroughbreds.

The aim of the present study was to correlate the levels of COMP and aggrecan as indicators of tissue damage, in synovial fluid (sf) from carpal joints of acutely lame racehorses, with macroscopical lesions of articular cartilage (OA), osteochondral fractures and ligament tears found at arthroscopy. Sixty-three lame horses [49 Standardbred trotters (STB) and 14 Thoroughbreds (TB)] in conventional training and racing that underwent arthroscopy of their middle carpal or radiocarpal joints were included in the study. Intact as well as fragmented COMP and aggrecan released into the synovial fluid were quantified by western blot analyses and ELISA. The expression of COMP in tissues was estimated by mRNA in situ hybridisation and protein immunolocalisation in cartilage and osteochondral fractures. The concentration of sf-COMP was higher in TB with an osteochondral fracture than in STB with osteochondral fractures and TB and STB with OA. The chondrocytes in middle and deep zones of the articular cartilage of the osteochondral fragments (from a TB) expressed COMP mRNA, in contrast to the cartilage on the opposite side of the fracture where no expression was detected. In the synovial fluid from a joint (TB) with osteochondral fractures only intact COMP was present, whereas, fragmented COMP was more prominent in synovial fluid from a joint with OA. The concentration of sf-aggrecan did not differ between the two breeds, or between different lesions. The increased concentration of sf-COMP in TB with osteochondral fractures, but not in synovial fluid from equine joints with OA, is a novel finding. The results from this study indicate that elevated sf-COMP concentration in the joints of Thoroughbreds may be a useful marker for carpal joint osteochondral fragments.

Differential adherence of osteoarthritis and rheumatoid arthritis synovial fibroblasts to cartilage and bone matrix proteins and its implication for osteoarthritis pathogenesis.

In osteoarthritis (OA), cartilage and bone fragments have been described within the synovial tissue which are surrounded by synovial cells (i.e. detritus synovitis). These cells appear to attach actively to the cartilage and bone fragments. In rheumatoid arthritis (RA), on the other hand, synovial fibroblasts (SF) have also been shown to be localized at sites of invasion into cartilage and bone and to degrade extracellular matrix (ECM) by secreting proteolytic enzymes. One prerequisite for exerting their aggressive properties is the attachment to cartilage and bone ECM. This attachment appears to be mediated by the expression of different adhesion molecules for which corresponding binding sites on ECM components are known. As it has not been addressed to which ECM proteins SF adhere and with which affinity this process takes place, we investigated the adherence of SF from patients with OA and RA to different cartilage and bone matrix proteins. Synovial tissue samples were obtained during synovectomy or arthroplastic surgery and used for isolating and culturing SF. Synovial cells attaching to cartilage/bone fragments were characterized using immunohistochemistry. The adherence of SF to ECM proteins was examined using an adhesion assay with the following proteins coated on 96-well plates: aggrecan (AGG), bone sialoprotein (BSP), cartilage oligomeric matrix protein (COMP), collagen type I, II and VI, proline arginine-rich, end leucine-rich repeat protein (PRELP), osteopontin (OPN) and recombinant chondroadherin (CHAD). Bovine serum albumin was used as negative control. In addition, adhering fibroblasts were photographed using a phase-contrast microscope. As compared with RA-SF, significantly higher numbers of OA-SF adhering to collagen type II, OPN and CHAD could be detected (P < 0.05). In contrast, RA-SF showed increased attachment to collagen type II, OPN and BSP. Adhesion to AGG, COMP and PRELP appeared not to be significantly increased and differed widely among the SF samples, and, apart from one exception (BSP), OA-SF adhered in higher numbers to the matrix proteins than did RA-SF. Using immunohistochemistry, synovial cells attached to cartilage/bone fragments could be shown to predominantly express CD68 (>/=50%). The CD68-negative population was of the fibroblast phenotype (AS02 positive). The study demonstrates that the binding pattern of OA-SF and RA-SF to ECM proteins differs considerably and therefore provides novel insights into the difficult pathophysiology of OA and RA. In general, it appeared that SF adhere primarily to ECM proteins that contain known binding sites for adhesion molecules (e.g. integrins: collagen/integrin alpha(2)beta(1)) and that higher numbers of OA-SF adhered to the cartilage and bone matrix proteins than did RA-SF.

Tenocyte response to cyclical strain and transforming growth factor beta is dependent upon age and site of origin.

The effect of strain and transforming growth factor beta on equine tendon fibroblasts (tenocytes) was assessed in vitro. Tenocytes were isolated from flexor and extensor tendons of horses from foetal to 10 years of age. These cells were cultured until confluent on collagen-coated silicone dishes. Cyclic biaxial strain of 9+/-1% was applied at 0.5 Hz for 24 hours with or without added TGFbeta1 or 3 (10 ng/ml). Proliferation and synthetic responses were dependent on the tendon of origin. Neither strain nor TGFbeta caused flexor tenocytes to proliferate significantly, while strain alone did proliferate extensor tenocytes. TGFbeta, with or without strain, increased the incorporation of [3H]-proline and the production of types I and III collagen and COMP in both cell types, although the effect on COMP production was more marked in flexor tenocytes, perhaps reflecting the higher levels found in this tendon in vivo. Immature flexor tenocytes synthesised more collagen and COMP than those from mature animals, while age had little effect in extensor tenocytes. Our results suggest that tenocytes become differentiated at an early age and present tendon-specific responses.

Extracellular matrix components in atherosclerotic arteries of Apo E/LDL receptor deficient mice: an immunohistochemical study.

During accelerated vascular remodeling such as in atherosclerosis, the composition of the extracellular matrix becomes altered. The matrix components of the diseased artery influence cellular processes such as adhesion, migration and proliferation. Furthermore, in atherosclerosis, the inability of the cells within the lesion to produce a mechanically stable matrix may lead to plaque rupture. In this immunohistochemical study of atherosclerotic mice aorta, we have reviewed the presence of ECM components with roles in maintaining tissue structure and function. These components include osteopontin and COMP as well as the leucine rich repeats proteins decorin, PRELP, and fibromodulin. Immunohistochemistry demonstrated presence of osteopontin, COMP, decorin, PRELP and fibromodulin in lesion areas of ApoE/LDLr deficient mice. Some advanced lesions exhibited areas of cartilage-like morphology and were shown to represent cartilage by their content of the cartilage specific proteins collagen II and aggrecan. The results suggest that cartilage-associated cell/collagen binding ECM proteins may be involved in the pathogenesis of atherosclerosis.

Ultrastructural distribution of osteoadherin in rat bone shows a pattern similar to that of bone sialoprotein.

Osteoadherin (OSAD) is a keratan sulfate proteoglycan recently isolated from bovine and rat bone. Based on results obtained from in vitro experiments, the protein was shown to bind osteoblasts via the integrin receptor alpha v beta 3. Due to OSAD's capacity to bind hydroxyapatite crystals, a role for the protein in the mineralization process has also been suggested. To test these hypotheses in an in vivo model, the ultrastructural localization of OSAD in bone, tibial (metaphyses and diaphyses), and calvarial samples from normal 10 to 12-day-old rats were examined by immunohistochemical techniques at the ultrastructural level. In addition to the qualitative studies, quantitative measurements of OSAD marker density were performed in relevant compartments. Immunolabeling for OSAD was located to the mineralized bone matrix, with highest concentration of marker at the border between bone and cartilage remnants in the metaphyseal trabeculi. Intracellular labeling was low and no systemic accumulation of OSAD markers was observed at the cell-matrix interface. The observed distribution pattern of OSAD is strikingly similar to that of bone sialoprotein (BSP), confirmed by double labeling. The results of the current study support a role for OSAD in the mineralization process. In this process BSP is assumed to be a nucleator of hydroxyapatite crystals, and OSAD could work in concert with BSP to regulate nucleation. However, the mechanisms involved remain to be elucidated.

The influence of ageing and exercise on tendon growth and degeneration--hypotheses for the initiation and prevention of strain-induced tendinopathies.

Strain-induced tendinopathy is a common injury in both human and equine athletes, with increasing incidence associated with greater involvement in sport and an increasingly aged population. This paper reviews our studies on the abundant non-collagenous protein, cartilage oligomeric matrix protein (COMP), in equine tendons. Its variation between tendon type and site, age and exercise has provided an insight into how age and exercise influence tendon growth and maturation. Tendons can be broadly divided into two types, reflecting their different matrix composition and function: the energy-storing tendons used for weight-bearing and locomotion, which suffer a high incidence of strain-induced tendinopathy, and positional tendons involved in limb placement or manipulative skills. It would appear that while energy-storing tendon can respond to the mechanical forces applied to it during growth, there is no evidence that it can do so after skeletal maturity. Instead, cumulative fatigue damage causes degeneration at the molecular level, potentially weakening it and increasing the risk of clinical injury. Appropriate exercise regimes early in life may help to improve the quality of growing tendon, thereby reducing the incidence of injury during ageing or subsequent athletic career.