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EQUINE VETERINARY EDUCATION / AE / SEPTEMBER 2017


Review Article


A review of the healing processes in equine superficial digital flexor tendinopathy


S. G. Dakin Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, University of Oxford, UK. Corresponding author email: stephanie.dakin@ndorms.ox.ac.uk


Keywords: horse; tendinopathy; inflammation; fibrosis


Summary Tendinopathy is a significant cause of morbidity and mortality in athletic and aged horses. These injuries require prolonged convalescence and heal by the formation of scar tissue instead of neo-tendon, predisposing to reinjury. This article reviews the biological processes involved in tendon healing and their implications for clinical practice to improve future treatment of these injuries.


Introduction


Tendon disease affecting the equine distal limb is a notoriously challenging clinical problem. Whilst exercise and ageing are important contributing factors to the development of tendon injury (Smith et al. 1999, 2014; Dudhia et al. 2007), incomplete understanding of the biological processes occurring in disease hampers the development of effective new therapies. Inflammation and fibrosis are key biological processes central to the healing of all tissues in the body after injury. Whilst inflammation and fibrosis have been well studied in animal models of tendinopathy, knowledge of these important biological pathways is limited in equine tendon disease.


Inflammation in tendinopathy: where is the evidence?


Prior to clinical symptoms, there is a phase of subclinical tendon pathology (Webbon 1977, 1978). Whilst not well understood, the balance at some stage tips from cumulative microscale damage and progresses to macroscale damage manifesting in clinical disease. At this acute symptomatic stage, horses frequently present with heat, pain and swelling in the region of the palmar metacarpal soft tissues. Lameness levels are variable and horses with acute SDFT injuries may have a short phase of severe lameness. Hyperextension of the metacarpophalangeal joint also occur and correlate with the severity of tendon pathology. The overt phase of clinical inflammation is frequently transient, lasting only days to weeks and is managed with limb support, box rest and anti- inflammatory drugs. An update of diagnosis and treatment for equine tendinopathy are discussed in detail elsewhere (Smith 2016). What biological processes are taking place within the


tendon at this time and how can this inform therapeutic rationale? A growing body of evidence suggests that inflammation is a key factor in the pathogenesis of human and equine tendon injury (Millar et al. 2009, 2010; Dakin et al.


© 2016 EVJ Ltd


2012b; Campbell et al. 2014; Thorpe et al. 2014). Inflammation involves recruitment of cell populations to debride the damaged tissue, orchestrating the repair process and triggering the resolution of inflammation such that the tissue returns to normal after injury (Levy et al. 2001). Studies of diseased equine superficial digital flexor tendons (SDFTs) have demonstrated inflammation is highly active at the cellular level, even after the clinical signs of inflammation including heat, pain and swelling of the tendon have subsided. Histological analysis of tissues from early stage tendinopathy (3–6 weeks after clinical onset) show injured equine SDFTs exhibit significant disruption of the tissue architecture and have increased cellularity compared with normal SDFTs (Dakin et al. 2012b) as illustrated in Figure 1. Characterisation of these cells in diseased tendons has shown an abundance of macrophages in the regions corresponding to core lesions. Analogous to wound healing processes in the skin, the phenotype of these macrophages in damaged equine SDFTs has been shown to change throughout the course of tendon healing. Macrophages in early stage equine tendon disease exhibit a proinflammatory phenotype, whereas a transition to an anti-inflammatory/profibrotic phenotype occurs in the later phases of tendon healing (Dakin et al. 2012b). Other immune cells such as B and T lymphocytes, mast cells and natural killer cells have been reported in samples of ruptured Achilles tendons in man (Kragsnaes et al. 2014). Increased vascularity and the release of stress signals including damage associated molecular patterns (DAMPS, Table 1) from the damaged tissues facilitate the infiltration of inflammatory cells to the injured site, permitting debridement of the injured zone through the release of proteolytic enzymes. After apoptosis and phagocytosis of dead cells, the reparative and remodelling phases ensue analogous to healing processes in skin. Immune cells such as macrophages are key cell types orchestrating this process. In the tissue remodelling phase, the phenotype of these highly plastic cells is more conducive to driving tissue repair (Lucas et al. 2010). A recent study characterised inflammation in human


shoulder tendinopathy illustrating diseased tendons show different inflammation signatures in early compared with advanced stage disease (Dakin et al. 2015). In this study inflammation was characterised using biomarkers representative of macrophage activation for pathways including Interferon, NF-jB, glucocorticoid receptor and STAT- 6 (Martinez and Gordon 2014; Murray et al. 2014) described in Table 1.Inflammation signatures in shoulder tendons in man revealed expression of genes and proteins induced by Interferon and NF-jB in early stage disease and genes and


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