Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture

Cell and Tissue Research, Oct 2017

The role of inflammation and the mechanism of tendon healing after rupture has historically been a matter of controversy. The purpose of the present study is to investigate the role of mast cells and their relation to the NMDA receptor-1 (a glutamate receptor) during healing after Achilles tendon rupture. Eight female Sprague Dawley rats had their right Achilles tendon transected. Three weeks after rupture, histological quantification of mast cell numbers and their state of degranulation was assessed by histochemistry. Co-localization of mast cell tryptase (a mast cell marker) and NMDA receptor-1 was determined by immunofluorescence. The intact left Achilles tendon was used as control. An increased number of mast cells and a higher proportion of degranulated mast cells were found in the healing Achilles tendon compared to the intact. In addition, increased co-localization of mast cell tryptase and NMDA receptor-1 was seen in the areas of myotendinous junction, mid-tendon proper and bone tendon junction of the healing versus the intact tendon. These findings introduce a possible role for mast cells in the healing phase after Achilles tendon rupture.

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Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture

Cell Tissue Res Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture Md. Abdul Alim 0 1 2 6 7 8 Paul W. Ackermann 0 1 2 6 7 8 Pernilla Eliasson 0 1 2 6 7 8 Parmis Blomgran 0 1 2 6 7 8 Per Kristiansson 0 1 2 6 7 8 Gunnar Pejler 0 1 2 3 6 7 8 Magnus Peterson 0 1 2 6 7 8 0 Department of Medical Biochemistry and Microbiology, Uppsala University , BMC Box 582, Uppsala , Sweden 1 Department of Molecular Medicine and Surgery, Karolinska Institutet , Solna , Sweden 2 Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University , 751 3 Stockholm , Sweden 4 Uppsala , Sweden 5 Magnus Peterson 6 Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences , Uppsala , Sweden 7 Department of Clinical and Experimental Medicine, Linköping University , Linköping , Sweden 8 Department of Orthopedics, Karolinska University Hospital , SE-171 7 The role of inflammation and the mechanism of tendon healing after rupture has historically been a matter of controversy. The purpose of the present study is to investigate the role of mast cells and their relation to the NMDA receptor-1 (a glutamate receptor) during healing after Achilles tendon rupture. Eight female Sprague Dawley rats had their right Achilles tendon transected. Three weeks after rupture, histological quantification of mast cell numbers and their state of degranulation was assessed by histochemistry. Co-localization of mast cell tryptase (a mast cell marker) and NMDA receptor-1 was determined by immunofluorescence. The intact left Achilles tendon was used as control. An increased number of mast cells and a higher proportion of degranulated mast cells were found in the healing Achilles tendon compared to the intact. In addition, increased co-localization of mast cell tryptase and NMDA receptor-1 was seen in the areas of myotendinous junction, mid-tendon proper and bone tendon junction of the healing versus the intact tendon. These findings introduce a possible role for mast cells in the healing phase after Achilles tendon rupture. Achilles tendon healing; NMDA; Mast cells; Tryptase; Rats Introduction The physiological mechanisms of tendon healing and pain signaling are still far from understood and the debate continues regarding the role of inflammation in healing and tendinopathy development (Abate et al. 2009; Millar et al. 2017) . Patients afflicted by acute Achilles tendon rupture (ATR) also exhibit variable and long-term impaired outcomes such as pain and fatigue (Alim et al. 2016). In peripheral tissues, the peripheral nerve system (PNS) exhibits a key role in regulating inflammation, pain signaling and healing of the damaged tissue via afferent to efferent pathways (Chiu et al. 2012) . Peripheral nerve endings at the site of injury can emit potent neuromediators with the ability to modify the function of fibroblast-like cells in the healing tendon tissue (Ackermann et al. 2014; Murphy and Hart 1993) . Emitted neuronal substances may also interact with resident mast cells (MCs) and macrophages to affect their function (Chiu et al. 2012; Murphy and Hart 1993) . Conversely, MCs contain substances that, when emitted, may alter the function of both the PNS and tissue cells (Hart et al. 1998) . It has been hypothesized that MCs residing near nerve endings may degranulate and affect the function of the PNS, which makes them a potential target for modulating inflammation and pain. Glutamate is the primary excitatory mediator of the nervous system and has, via its preferred receptor, NMDAR1, been implicated in regulating tendon healing (Ackermann et al. 2014; Molloy et al. 2006b) and various pain conditions (Freemont et al. 1997) including tendinopathy (Ackermann et al. 2014) . In tendon healing as well as in tendinopathic patients, a 10-fold up-regulation of NMDAR1 expression has been established (Greve et al. 2012; Molloy et al. 2006a) . In tendinopathy, NMDAR1 has been observed in morphologically transformed tenocytes in the endothelial and adventitial layers of neovessel walls and in presumed sprouting nerve fibers (Murphy and Hart 1993). The nerve ingrowth in combination with the downstream effect of NMDAR1 activation may represent an important physiological regulation mechanism operative in tendon healing, pain regulation and maybe also in tendinopathy. We hypothesize that there may exist a link between NMDAR1 and MC activation in tendon healing. The aim of this study is therefore to investigate the possible role of MCs in tendon healing. To this end, we used a rat model of ATR and investigated the presence and state of activation of MCs during the healing process. Moreover, the potential communication between MCs and nerve cells was addressed by assessing the spatial relation between MCs and NMDAR1. Materials and methods Study design An animal model for ATR was used to q (...truncated)


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Md. Abdul Alim, Paul W. Ackermann, Pernilla Eliasson, Parmis Blomgran, Per Kristiansson, Gunnar Pejler, Magnus Peterson. Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture, Cell and Tissue Research, 2017, pp. 451-460, Volume 370, Issue 3, DOI: 10.1007/s00441-017-2684-y