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Chemokine expression of CCL2, CCL3, CCL5 and CXCL10 during early inflammatory tendon healing precedes nerve regeneration: an immunohistochemical study in the rat

  • Experimental Study
  • Published:
Knee Surgery, Sports Traumatology, Arthroscopy Aims and scope

Abstract

Purpose

Chemokines are major promoters of repair and may regulate nerve ingrowth that is essential in tendon healing. The purpose of this study was to assess the temporal occurrence of different chemokines during Achilles tendon healing in relation to sensory nerve regeneration. Chemokine presence in tendon healing has not been studied previously.

Methods

Chemokine expression, nerve regeneration, angiogenesis and inflammatory cell occurrence during healing of Achilles tendon rupture in the rat were studied by immunohistochemistry and histology including semiquantitative assessment. Markers for chemokines (CCL5, CCL2, CCL3, CXCL10), nerves (PGP-9.5) and sensory neuropeptide substance P (SP) were analysed at different time points (1 day–16 weeks) post-rupture.

Results

In intact tendons (controls) immunoreactivity to all chemokines, PGP-9.5 and SP were confined to the tendon surroundings. After rupture, there was rapid increase in the tendon proper of the chemokines studied, all exhibiting their peak expression at week 1. Subsequently, at weeks 2–6, emerging inflammatory cells and maximum sprouting of PGP-/SP-positive nerves were observed close to newly formed blood vessels within the tendon proper, while chemokine expression already decreased. During weeks 6–8, PGP-/SP-positive nerves withdrew from the rupture site and relocated together with the chemokines in the surrounding tendon.

Conclusions

Early chemokine expression in the healing tendon precedes ingrowth of new nerves, angiogenesis and emergence of inflammatory cells. The fine-tuned temporal and spatial appearance of chemokines suggests a chemoattractant role for inflammatory cell migration and possibly also a role in angiogenesis and neurogenesis. Chemokines may thus exhibit vital targets for biological modulation of tendon repair.

Level of evidence

III.

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Acknowledgments

This study was supported by the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet (project nr. SLL20100168) and the Swedish National Centre for Sports Research as well as the Swedish Research Council (project nr. 2012-3510).

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Authors and Affiliations

  1. Department of Clinical Science Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden

    A. Stålman

  2. Aleris Sabbatsberg Hospital, Stockholm, Sweden

    A. Stålman

  3. Integrative Orthopedic Laboratory, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

    D. Bring & P. W. Ackermann

  4. Orthopedic Department, Karolinska University Hospital, Stockholm, Sweden

    D. Bring & P. W. Ackermann

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  1. A. Stålman
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  2. D. Bring
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  3. P. W. Ackermann
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Correspondence to A. Stålman.

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Stålman, A., Bring, D. & Ackermann, P.W. Chemokine expression of CCL2, CCL3, CCL5 and CXCL10 during early inflammatory tendon healing precedes nerve regeneration: an immunohistochemical study in the rat. Knee Surg Sports Traumatol Arthrosc 23, 2682–2689 (2015). https://doi.org/10.1007/s00167-014-3010-9

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  • DOI: https://doi.org/10.1007/s00167-014-3010-9

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