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Evidence of the TNF-α system in the human Achilles tendon: expression of TNF-α and TNF receptor at both protein and mRNA levels in the tenocytes
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
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2012 (English)In: Cells Tissues Organs, ISSN 1422-6405, E-ISSN 1422-6421, Vol. 196, no 4, 339-352 p.Article in journal (Refereed) Published
Abstract [en]

Understanding adaption to load is essential for prevention and treatment of tendinopathy/tendinosis. Cytokine release in response to load is one mechanism involved in mechanotransduction. The cytokine tumor necrosis factor alpha (TNF-α) is implicated in tendinosis and can induce apoptotic effects via tumor necrosis factor receptor 1 (TNFR1). The complete absence of information concerning the TNF-α system in Achilles tendon is a limitation as mid-portion Achilles tendinosis is very frequent. Purpose: To examine expression patterns of TNF-α and its two receptors (TNFR1 and TNFR2) in human Achilles tendinosis and control tissue and to biochemically confirm the presence of TNF-α in tendinosis tissue. Methods: TNF-α and TNFR1 mRNA were detected via in situ hybridization. TNF-α, TNFR1, and TNFR2 were demonstrated immunohistochemically. Apoptosis markers were utilized. ELISA was used to detect TNF-α. Results: TNF-α and TNFR1 mRNA was detected in tenocytes of both tendinosis and control tendons. Tenocytes from both groups displayed specific immunoreactions for TNF-α, TNFR1, and TNFR2. The widened/rounded tenocytes of tendinosis samples exhibited the most intense immunoreactions. Apoptosis was detected in only a subpopulation of the tenocytes in tendinosis tissue. TNF-α was measurable in tendinosis tissue. Inflammatory cells were not seen. Conclusion: This is the first evidence of the existence of the TNF-α system in the human Achilles tendon. Findings are confirmed at mRNA and protein levels as well as biochemically. The TNF-α system was in principle confined to the tenocytes. The connection between tenocyte morphology and the expression pattern of TNF-α, TNFR1, and TNFR2 suggests that the TNF-α system may be involved in tenocyte activation in Achilles tendinosis.

Place, publisher, year, edition, pages
S. Karger, 2012. Vol. 196, no 4, 339-352 p.
Keyword [en]
Achilles tendon, Tendinopathy, Cytokine, TNF-α, TNFR1, TNFR2, Apoptosis
National Category
Medical and Health Sciences
URN: urn:nbn:se:umu:diva-55439DOI: 10.1159/000335475ISI: 000309035500004PubMedID: 22572155OAI: diva2:526804
Available from: 2012-05-15 Created: 2012-05-15 Last updated: 2013-01-04Bibliographically approved
In thesis
1. TNF-α and neurotrophins in Achilles tendinosis
Open this publication in new window or tab >>TNF-α and neurotrophins in Achilles tendinosis
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Tenocytes are the principal cells of the human Achilles tendon. In tendinosis, changes in the metabolism and morphology of these cells occur. Neurotrophins are growth factors essential for the development of the nervous system. Tumour necrosis factor alpha (TNF-α) has been found to kill sarcomas but has destructive effects in several major diseases. The two systems have interaction effects and are associated with apoptosis, proliferation, and pain signalling in various diseases. Whether these systems are present in the Achilles tendon and in Achilles tendinosis is unknown. The hypothesis is that the tenocytes produce substances belonging to these systems. In Studies I–III, we show that the potent effects of these substances are also likely to occur in the Achilles tendon. We found tenocyte immunoreactions for the neurotrophins brain-derived neurotrophic factor (BDNF), the nerve growth factor (NGF), the neurotrophin receptor p75, and for TNF-α and both of its receptors, TNFR1 and TNFR2. This occurred in both subjects with painful mid-portion Achilles tendinosis, and in controls. Furthermore, we found mRNA expression for BDNF and TNF-α in tenocytes, which proves that these cells produce these substances. TNFR1 mRNA was also detected for the tenocytes, and TNFR1 immunoreactions were upregulated in tendinosis tendons. This might explain why tenocytes in tendinosis undergo apoptosis more often than in normal tendons. Total physical activity (TPA) level and blood concentration of both soluble TNFR1 and BDNF were measured in Study IV. The results showed that the blood concentration of both factors were similar in subjects with tendinosis and in controls. Nevertheless, the TPA level was related to the blood concentration of sTNFR1 in tendinosis, but not in controls. This relationship should be studied further. The findings of this doctoral thesis show that neurotrophin and TNF-α systems are expressed in the Achilles tendon. We believe that the functions include tissue remodelling, proliferation and apoptosis.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2013. 121 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1538
Achilles tendon, tendinosis, tendinopathy, neurotrophins, TNF-alpha, physical acitivity, apoptosis, proliferation, pain, remodelling
National Category
Basic Medicine
Research subject
Human Anatomy
urn:nbn:se:umu:diva-63660 (URN)978-91-7459-525-3 (ISBN)
Public defence
2013-01-25, Biologihuset, sal BiA201, Umeå universitet, Umeå, 09:00 (Swedish)
Available from: 2013-01-04 Created: 2013-01-03 Last updated: 2014-12-18Bibliographically approved

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