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Microtrauma stimulates rat Achilles tendon healing via an early gene expression pattern similar to mechanical loading
Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
2014 (English)In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 116, no 1, p. 54-60Article in journal (Refereed) Published
Abstract [en]

Mechanical loading increases the strength of healing tendons, but also induces small localized bleedings. Therefore, it is unclear if increased strength after loading is a response to mechanotransduction or microtrauma. We have previously found only five genes to be up-regulated 15 min after a single loading episode, of them four were transcription factors. These genes are followed by hundreds of genes after 3 h, many of them involved in inflammation. We now compared healing in mechanically unloaded tendons with or without added microtrauma induced by needling of the healing tissue. Nineteen rats received Botox into the calf muscle to reduce loading, and the Achilles tendon was transected. Ten rats were randomized to needling days 2-5. Mechanical testing on day 8 showed increased strength by 45% in the needling group. Next, another 24 rats were similarly unloaded, and 16 randomized to needling on day 5 after transection. Nineteen characteristic genes, known to be regulated by loading in this model, were analyzed by qRT-PCR. Four of these genes were regulated 15 min after needling. Three of them (Egr1, c-Fos, Rgs1) were among the five regulated genes after loading in a previous study. Sixteen of the 19 genes were regulated after 3 h, in the same way as after loading. In conclusion, needling increased strength, and there was a striking similarity between the gene expression response to needling and mechanical loading. This suggests that the response to loading in early tendon healing can, at least in part, be a response to microtrauma.

Place, publisher, year, edition, pages
American Physiological Society , 2014. Vol. 116, no 1, p. 54-60
Keyword [en]
qRT-PCR; unloading; mechanical testing; early response genes; inflammation
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-103870DOI: 10.1152/japplphysiol.00741.2013ISI: 000329196100008OAI: oai:DiVA.org:liu-103870DiVA, id: diva2:692536
Available from: 2014-01-31 Created: 2014-01-30 Last updated: 2018-02-20
In thesis
1. Tendon Healing: Mechanical Loading, Microdamage and Gene Expression
Open this publication in new window or tab >>Tendon Healing: Mechanical Loading, Microdamage and Gene Expression
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mechanical loading and the inflammatory response during tendon healing might be important for the healing process. Mechanical loading can improve the healing tendon but the mechanism is not fully understood. The aim of this thesis was to further clarify the effect of mechanical loading on tendon healing and how mechanical loading affects the inflammatory response during the healing process.

We used a rat Achilles tendon model to study healing. The rats were exposed to different degrees of loading by unloading methods such as paralysis of the calf muscles with Botox, tail suspension, and an orthosis (a boot). Full loading was achieved by free cage activity or treadmill walking. Microdamage in tendons, unloaded with Botox, was also investigated by needling. The healing tendons were evaluated in a materials testing machine (to analyze the mechanical properties), by gene expression analysis (microarray and PCR), or histology.

Our results show that moderate loading (unloading with Botox) improves the mechanical properties of healing tendons compared to minimal loading (unloading with Botox in combination with tail suspension or a boot), especially the material properties. In accordance to these findings, expression of extracellular matrix genes were also increased by moderate compared to minimal loading.

Full loading improved all mechanical properties and the expression of extracellular matrix genes was further increased compared to moderate loading. However, structural properties, such as the strength and the size of the healing tendon, were more affected by full loading. Full loading also affected the expression of inflammation-related genes during the early healing phase, 3 and 5 days after tendon injury, and increased the number of immune cells in the healing tendon tissue. Also microdamage of the healing tendon (detected by blood leakage) was increased by full loading compared to moderate loading during the early healing phase.

Induced microdamage by repeated needling in the healing tendon tissue increased the structural properties of the healing tendon. The gene expression after needling was similar to the gene expression after full loading.

The improvement of mechanical properties by loading in healing tendons was decreased by an anti-inflammatory drug called parecoxib, which decreases the production of prostaglandins by inhibiting COX-2 activity. The effect of parecoxib was reduced when loading was reduced but we could not confirm that the effect of parecoxib was related to the degree of loading. However, parecoxib abolished the stimulatory effect of microdamage.

In conclusion, these studies show that moderate loading improves the quality of the healing tendon whereas full loading also increases the quantity of the healing tendon tissue. Full loading creates microdamage and increases inflammation during the early healing phase. The strong effect of full loading on the structural properties might be due to microdamage. Indeed, the anti-inflammatory drug parecoxib seems to impair mechanical stimulation of healing tendons by reducing the response to microdamage.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 28
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1609
National Category
Biomaterials Science
Identifiers
urn:nbn:se:liu:diva-145281 (URN)10.3384/diss.diva-145281 (DOI)9789176853610 (ISBN)
Public defence
2018-03-26, Belladonna, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-02-28Bibliographically approved

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Hammerman, MalinAspenberg, PerEliasson, Pernilla

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Division of Inflammation MedicineFaculty of Health SciencesDepartment of Orthopaedics in Linköping
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