Effect of anti-inflammatory medication on the
running-induced rise in patella tendon collagen synthesis
in humans

Britt Christensen, Sune Dandanell, Michael Kjaer and Henning Langberg
110:137-141, 2011. First published 28 October 2010; J Appl Physiol doi: 10.1152/japplphysiol.00942.2010 You might find this additional info useful.
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J Appl Physiol 110: 137–141, 2011.
First published October 28, 2010; doi:10.1152/japplphysiol.00942.2010.
Effect of anti-inflammatory medication on the running-induced rise in patella Britt Christensen,1,2 Sune Dandanell,1,3 Michael Kjaer,1 and Henning Langberg1
1Institute of Sports Medicine Copenhagen, Bispebjerg Hospital, and Center of Healthy Aging, University of Copenhagen,
Copenhagen, Denmark;
2Department of Endocrinology and Internal Medicine, NBG/THG, Aarhus University Hospital,
Aarhus, Denmark; and
3Faculty of Health, Care and Rehabilitation, School of Physiotherapy, Metropolitan University
College, Copenhagen, Denmark

Submitted 16 August 2010; accepted in final form 24 October 2010 Christensen B, Dandanell S, Kjaer M, Langberg H. Effect of anti-
(10), which have been shown to stimulate the synthesis of inflammatory medication on the running-induced rise in patella tendon collagen, at least in vitro. We have performed a number of collagen synthesis in humans. J Appl Physiol 110: 137–141, 2011. First studies on humans showing that several of the above-men- published October 28, 2010; doi:10.1152/japplphysiol.00942.2010.— tioned growth factors are increased in concentration in re- NSAIDs are widely used in the treatment of inflammatory diseases as sponse to exercise (8, 19 –21, 23).
well as of tendon diseases associated with pain in sports and labor.
However, the effect of NSAID intake, and thus blockade of PGE production, on the tendon tissue adaptation is unknown. The purpose involved in the inflammatory response in humans (6). Newly of the present study was to elucidate the possible effects of NSAID performed studies have demonstrated that prostaglandin con- intake on healthy tendon collagen turnover in relation to a strenuous centration in plasma or interstitial tissue can be blocked by bout of endurance exercise. Fifteen healthy young men were randomly ingestion or local infusion of NSAID (20, 30). Studies in assigned into two experimental groups, with one group receiving skeletal muscle have shown that NSAID can block the adaptive indomethacin (oral 2 ϫ 100 mg Confortid daily for 7 days; NSAID; activation of satellite cells, the stem cell of skeletal muscles, n ϭ 7) and a placebo group (n ϭ 8). Both groups were exposed to a and thus reduce the hypertrophy of skeletal muscle in response prolonged bout of running (36 km). The collagen synthesis NH2- to loading (27). Whether PGs play a role in the adaptive terminal propeptide of type I (PINP) and PGE2 concentrations were response in connective tissue is at present, however, not measured before and 72 h following the run in the patella tendon by known. NSAID is often the drug of choice in the treatment of microdialysis. The peritendinous concentrations of PINP increased inflammation, e.g., tendinopathies, soft tissue, and ligamentous significantly in the placebo group as a result of the run, as shown injuries (3). Considering the wide use of NSAID, the physio- previously. PGE2 levels were significantly decreased 72 h after the runcompared with basal levels in the subjects treated with NSAID and logical effects of this drug on the tendon tissue are important to unchanged in the placebo group. The NSAID intake abolished the understand for optimizing the treatment of patients with ten- adaptive increase in collagen synthesis in the patella tendon found in dinopathies and other tendon disorders (34). However, a full the placebo group in response to the prolonged exercise (P Ͻ 0.05).
understanding of the effects of PGE2 and the use of NSAID in The present study demonstrates that intake of NSAID decreased relation to mechanical loading in healthy tendon tissue is interstitial PGE2 and abolished the exercise-induced adaptive increase needed before it is possible to understand the pathology fully.
in collagen synthesis in human tendons.
The purpose of the present study was to analyze the effect of NSAID on the local peritendinous concentrations of PGE2 andpatella tendon collagen synthesis in response to an acute boutof endurance training. This was done to clarify the relationship HUMAN SKELETAL MUSCLES AND tendons are both known to between collagen synthesis and PGE2 levels by monitoring the respond and adapt to altered levels of physical activity by, e.g., effect on collagen synthesis when PGE2 release is blocked by hypertrophy and increased collagen synthesis (18, 29). Several NSAID. Based on previous findings, it was hypothesized that studies have shown that acute bouts of exercise, as well as the treatment with NSAID would lead to a decrease in PGE2 prolonged training, induces changes in local metabolism, in- levels. Given that PGE2 is a growth factor for collagen tissue, flammatory activity, and collagen turnover in the Achilles NSAID treatment would then lead to a decrease in the exercise- tendon (14, 24), resulting in an increased formation of type I induced increase in collagen synthesis.
collagen in the hours and days following the loading (14, 24,32). Along the same line, the human patella tendon has also been shown to demonstrate adaptive potential with markedly Subjects. A total of 15 healthy young men were included in the increased collagen synthesis in response to exercise (31). This present study (Table 1). They were randomly assigned into two groups transformation of mechanical forces to biochemical and struc- (by envelope): one group (n ϭ 8) receiving placebo (calcium tablets) tural responses (15) involves a number of different growth and the other group (n ϭ 7), indomethacin (oral intake starting 72 h factors (18), such as IGF-I (1), transforming growth factor-␤ prior to exercise and continuing 72 h postexercise; 100 mg Confortid (TGF-␤) (14, 36), PDGF-bb (5), IL-6 (Andersen MB, Pingel J, twice a day). Indomethacin is an NSAID that inhibits both cycloox- Kjaer M, Laugberg H, unpublished observation), and IL-1␤ ygenase-1 (COX-1) and COX-2 and thereby the production of PGE2.
The included subjects were all experienced runners, were training fora marathon, and were able to run 36 km in less than 3 h. None of thesubjects suffered from any tendon injuries within the last year or had Address for reprint requests and other correspondence: H. Langberg, Insti- tute of Sports Medicine Copenhagen, Bispebjerg Hospital, Bispebjerg bakke been taking any kind of medication within the last half year. All 23, 2400 Copenhagen NV, Denmark (e-mail: [email protected]).
subjects gave written informed consent to participate in the study after 8750-7587/11 Copyright 2011 the American Physiological Society TENDON COLLAGEN SYNTHESIS AND ANTI-INFLAMMATORY TREATMENT before usage (ETO sterilization). The peritendinous concentrations ofthe marker for collagen synthesis PINP and PGE2 were calculated using the internal reference method (37) as previously described (24).
Measurements of PGE2. PGE2 concentrations in dialysate from the peritendinous tissue of the patella tendons were measured with the PGE2 EIA kit (monoclonal, cat. no. 514010; Cayman Chemical).
Samples were diluted 1:5 before analysis, and all samples from the same subject were analyzed in the same assay. Intra-assay variation(coefficient of variation) was 3.9%, and the interassay variation was Values are means Ϯ SE. BMI, body mass index. There were no statistical 6.4% at 500 pg/ml. The detection level of the kit was 15 pg/ml.
significant differences between the 2 groups (P Ͼ 0.05).
Measurements of collagen synthesis. ELISA measured peritendi- nous concentrations of PINP, a marker for collagen synthesis, as receiving both written and oral information, in adherence to the previously described (33). Concentrations were measured in the dia- declaration of Helsinki. The local human subject ethics committee of lysate (local peritendinous concentration), which were diluted (1:8) Copenhagen and Frederiksberg approved the study.
before analysis. Samples from the same subject were analyzed in the Study design. Each subject completed a total of four experimental same assay. The detection level was 41 pg/ml and the intra-assay days. On the first day, the subjects had their aerobic capacity mea- variation (coefficient of variation) was 4.9% at 4.2 ng/ml (33).
sured on a treadmill. A minimum of 1 wk later, the collagen synthesis Statistics. The level of statistical significance was set to P Ͻ 0.05.
was measured at rest by the microdialysis method. The amount of All results are represented as means Ϯ SE. A student’s unpaired t-test collagen synthesis was determined in the peritendinous tissue ven- was used to analyze for differences in anthropometric data between trally to the patellar tendon. It was randomized in whichever leg the the two groups. Differences between the placebo and NSAID group in collagen synthesis was determined. At least 1 wk later, the subjects regard to PINP and PGE2 levels, respectively, were analyzed by a performed the 36 km of running; a route of 12 km was run a total of two-way ANOVA on ln-transformed data with Tukey’s post hoc test.
three times. At 72 h after completion of the run, the collagen synthesis SigmaPlot 11.0 was used for statistical analysis and graphical presen- was measured again by microdialysis in the patella tendon.
Placebo/NSAID was taken the first time 3 days before the 36-km run and until the last experimental day was conducted (1 pill every morning and evening). Hence, the measurements of collagen synthesisbefore running (baseline) were conducted before treatment with Subjects. There were no significant differences in anthropo- NSAID and thereby not affected by the treatment. All subjects were metric data (height, weight, age, body mass index, and V interviewed at the last day of the project to ensure that the protocol for between the two groups (P Ͼ 0.05) (Table 1).
intake of medication was followed and full compliance was found.
PGE2 blockade in the patella tendon. Local tissue concen- Measurements of aerobic capacity. Aerobic capacity was measured trations of prostaglandin were measured in the peritendinous as previously described (16). The participants performed a maximal space of the patella tendon at rest and 72 h after the 36 km of run at a constant speed of 130% of the self-reported speed on a 10-km running, both in relation to treatment with placebo and NSAID.
run, which should ensure that exhaustion would occur within 5 to 7min. After the first 2 min of running, the incline of the treadmill was There was a significant decrease in PGE2 levels after the 36-km adjusted to 2% and then increased by 2% every 1.5 min until run in the NSAID group (497 Ϯ 149 to 132 Ϯ 26 pg/ml) (P Ͻ exhaustion. Respiratory variables were measured continuously (AMIS 0.001); however, PGE2 levels were unchanged in the placebo 2001 automated metabolic cart; Innovation, Odense, Denmark) and group (317 Ϯ 107 to 331 Ϯ 111 pg/ml) (P Ͼ 0.05) (Fig. 1, A averaged for each 30-s period. The mean of the three highest mea- ˙ O2 was used as the peak oxygen consumption Effects of PGE2 blockade on collagen synthesis in the patella tendon. The peritendinous concentrations of PINP in- Microdialysis. The microdialysis method was used in the present creased significantly in the placebo group (39 Ϯ 11 to 100 Ϯ study to determine collagen synthesis in the peritendinous tissue of the 20 ng/ml) (P ϭ 0.002), but this increase was abolished in the patella tendon and was performed in principle as described previously NSAID group (18 Ϯ 5 to 11 Ϯ 3 ng/ml) (P Ͼ 0.05). The (26). Before insertion of the microdialysis catheter the skin on bothsides of the patella tendon was anesthetized using local anesthesia overall effect of the treatment was significant (P ϭ 0.004). No (lidocaine). The microdialysis catheters were positioned ventral and as statistical difference at rest (P Ͼ 0.05) was found between the close to the patella tendon as possible using ultrasound guidance.
placebo and NSAID group; however, a significant difference at During the experiment, the actual flow in the microdialysis catheters 72 h postrunning (P Ͻ 0.001) was found between the groups were monitored by weighing the veils used for collecting the samples before and after the experiment. For each sample a correction factorwas calculated and used to determine the in vivo recovery of NH2- DISCUSSION
terminal propeptide of type I collagen (PINP) and PGE2 using theinternal reference method (37). The factor was determined as the The main finding of the present study is the demonstration of exchange rate over the membrane of the microdialysis fiber. Three a total blunting of the exercise-induced increase in collagen nanomolar 3H-labeled human type IV collagen (130 kDa; specific synthesis in the patella tendon following an intake of NSAID.
activity: 7.0 TBq mgϪ1; NEN, Boston, MA) was added to the The intake of NSAID leads to a reduction in the PGE2 pro- perfusate to determine the relative loss. A high precision syringe duction and this was associated with a decreased collagen pump (model CMA100) insured a perfusion rate of 2 ␮l/min. Dialy- sate was collected for a total of 4 h of which the last 3.5 h were used The present study showed that an acute prolonged bout of for analysis minimizing the possible effects of the insertion of themicrodialysis catheter. The dialysate was immediately frozen at endurance exercise (36 km running) induced an increase in Ϫ80°C until subsequent analyses were performed.
collagen synthesis in the patella tendon (Fig. 2). This is in The microdialysis catheters used in the present study were custom- accordance with previous studies showing that Achilles tendon made as previously described (24). The catheters were sterilized tissue responds upon an acute bout of different types of J Appl Physiol • VOL 110 • JANUARY 2011 • TENDON COLLAGEN SYNTHESIS AND ANTI-INFLAMMATORY TREATMENT Fig. 1. PGE2 blockade in the patella tendon. Mea-surements of patella tendon peritendinous concen-trations of PGE2 before and 72 h after a 36-km runafter placebo treatment (n ϭ 5) (A) and NSAIDtreatment (n ϭ 6) (B). Bars represent means Ϯ SE,*P Ͻ 0.05.
exercise (14, 24, 32) as well as prolonged training (22) by collagenase levels increased, while the hydroxyproline content increasing collagen type I synthesis. In addition, studies using was unchanged, indicating a net increase in collagen degrada- the infusion of stable isotopes, potentially a more direct mea- tion after stretching of avian flexor digitorum profundus ten- sure of collagen synthesis, showed the same adaptive response dons (8). This could indicate that the increased PGE2 produc- to a 1-h kicking exercise in the patella tendon with increased tion seen in relation to exercise/stretching could play some role in tendon collagen degeneration. In support of PGE2 being a The adaptive response in collagen synthesis in human ten- growth factor for collagen synthesis, previous in vitro studies dons to loading is thought to be mediated through a combina- have shown that blockade of PGE2 release by indomethacin tion of a direct mechanical effect on the load on the fibroblasts results in a decrease in DNA synthesis (4), cell proliferation, and the release of various substances, such as different cyto- and tendon glycosaminoglycan synthesis (35). Thus, the in- kines (e.g., IL-6) and growth factors (e.g., TGF-␤, IGF-I) (28).
crease in collagen synthesis in the present study could be partly PGE2 levels have been shown to be elevated during and mediated through the increase in PGE2. Several studies have immediately after exercise locally in the peritendinous tissue analyzed the effect of PGE2 blockade on the collagen tissue (20, 23, 24) and thus potentially play a role in the exercise- supporting the findings from the present study. In a study by induced adaptive response in collagen synthesis (14, 22, 24, 31, Ferry et al. (9) it was found that COX-2 inhibitors given in the 32). As PGE2 concentration can be manipulated by reducing postoperative period after injury at the osteotendinous junction the interstitial concentration through an intake of NSAID (13), in rabbits, resulted in significantly decreased levels of hy- it is possible to test this hypothesis. Several studies have stated droxyproline, a marker for collagen synthesis, compared with that a prolonged run as the present one used leads to an the placebo group. This resulted in a detrimental effect on increased release of various inflammatory factors (11, 21, 23).
tendon healing strength, with the tendons treated with COX-2 In addition, in vitro studies have shown that a regimen of cyclic inhibitors being significantly weaker than the control tendons mechanical stretching of human tendon fibroblasts results in an (9). In a rat study by Forslund et al. (12), it was found that increased production of PGE2 and COX by the fibroblasts in a indomethacin treatment resulted in a significantly reduced stretching frequency-dependent manner (4, 25, 39).
cross-sectional area of the tendon regenerate, but failure load The consequences of these elevated levels of PGE2 during was unchanged. On the other side, protein synthesis (measured exercise have been addressed in previous studies, showing that as an increase in 3H-proline incorporation) has been found to rabbit tendons injected with PGE2 had a predominant pattern of be increased, which could indicate that the synthesis of colla- degeneration in the tendon matrix, with a decreased collagen gen molecules is actually stimulated by PGE2 inhibition (4).
fibril diameter and loss of parallel collagen fiber organization In the present study, the intake of NSAID lead to a (17). This is supported by additional studies showing that significant reduction in the exercise-induced collagen syn- exogenous PGE2 decreased both the in vitro proliferation of thesis in the patella tendon (Fig. 2). Unfortunately, no human patellar tendon fibroblasts and the collagen production measurements were performed immediately after exercise in compared with the placebo group (7). Furthermore, PGE2 and the present study, but a significant lowering of the PGE2 Fig. 2. Effects of PGE2 blockade on collagensynthesis in the patella tendon. Measurements ofperitendinous propeptide of type I (PINP) before and 72 h after a36-km run and placebo treatment (n ϭ 6) (A) orNSAID treatment (n ϭ 7) (B). Bars representmeans Ϯ SE, *P Ͻ 0.05.
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