Histologic grading correlates with inflammatory biomarkers in tibialis posterior tendon dysfunction
Introduction
Insufficiency of the tibialis posterior tendon (TPT) results in the painful clinical entity known as tibialis posterior tendon dysfunction (TPTD). Degeneration, biomechanical failure and potential rupture of the TPT leads to progressive deformity of the foot and ankle known as adult-acquired flat foot deformity (AAFD), or progressive collapsing foot deformity (PCFD) [1], [2], [3], [4]. The explicit etiology of the degeneration of the TPT, or of any tendinopathy, is currently unknown, but is likely to be multifactorial. There are a number of contributory factors including overuse, repetitive strain, abnormal alignment, hypovascularity, increased free radical damage, gender, and genetics [5]. Moreover, TPTD is known to be associated with obesity, diabetes mellitus, hypertension, steroid exposure, and previous trauma or surgery to the medial foot [1].
Currently, the most widely accepted theory of tendinopathy is the mechanical strain theory [5]. The theory suggests that heavy loading of the tendon may result in the initial microtrauma to tendon extracellular matrix or cells. Repetitive heavy loading then leads to progressive damage and microtearing as the excessive wear overwhelms the tendon’s ability to heal. The accumulation of microscopic injury leads to macroscopic injury, degeneration and tears, particularly in the region of tendon distal to the medial malleolus, which correlates to an area of hypovascularity as identified by Frey, Shereff and Greenidge [6], [7].
However, the link to painful symptoms from mechanical loading, microscopic injury and degeneration is currently unknown. While tendinopathy was once considered to be a non-inflammatory process, newer evidence suggest that pain-related inflammatory cytokines, matrix metalloproteases (MMPs), pain neurotransmitters and angiogenesis are highly associated with tendinopathy [5], [8], [9], [10]. Also of interest are numerous studies that have demonstrated increased expression of pain neurotransmitters or receptors, such as glutamate, N-methyl-D-aspartate receptor type 1 (NMDAr1), substance P (SP), and calcitonin-gene-related-peptide (CGRP) in Achilles, patellar, extensor carpi radialis brevis, and carpal tunnel tendons [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23].
There is still much unknown about tendinopathy, especially the TPT in TPTD. The objective of this study was to characterize a subset of inflammatory cytokines, MMPs, and pain neurotransmitters that may be involved in mediating the symptoms of TPTD in a cohort of patients presenting with symptomatic stage II TPTD undergoing FDL tendon transfer. Additionally, no prior information is available on a potential role for the tendon insertion in contributing to altered biochemistry with tendinopathy as the current literature is based on non-insertional tendinopathy. Thus, a secondary objective of this study was to test for involvement of the TPT insertion in the degenerative and pain processes of TPTD. Determining the etiology and pathophysiology of painful TPTD could lead to better non-operative treatments for TPTD and tendinopathy in general, such as better drug therapy or injections which are currently still in the investigational stages [24], [25].
Section snippets
Patients & sample collection
Institutional review board approval was obtained prior to prospectively enrolling patients. To be included in this study, patients had to have stage 2 TPTD, as defined by Bluman et al., that failed at least 6 months of conservative management prior to undergoing FDL tendon transfer surgery [26]. Patients with more advanced disease, underwent arthrodesis, rheumatological diseases, or were below the age of 18 were excluded. Trimmings from the mid-substance of the transferred FDL tendon, diseased
Results
Samples were obtained from 21 (15 female, 6 male) patients undergoing flexor digitorum longus (FDL) tendon transfer for stage 2 TPTD that failed non-operative management. The average subject age was 64.3 years with a range of 53–76. The average mass and range of the healthy FDL samples was 0.34 g, and 0.15–1.18 g respectively. Average mass and range for the diseased TPT samples was 0.45 g and 0.19–0.73 g respectively. The average mass and range for the insertional TPT were 0.46 g and
Discussion
The cytokines IL-1β, IL-6, IL-8, IL-10, and TNF-α and matrix metalloproteases MMP-1, MMP-2, and MMP-3 were all significantly elevated in diseased TPT and TPT insertion compared to the transferred FDL tendon. This data is consistent with much of the literature concerning tendinopathy. Significantly increased levels of inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α), have been found in other tendinopathic tendons, while the reported data on interleukin-6
Funding statement
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declarations of interest
None relevant.
References (38)
- et al.
The effects of prolonged peritendinous administration of PGE1 to the rat Achilles tendon: a possible animal model of chronic Achilles tendinopathy
J Orthop Sci: J Jpn Orthop Assoc
(2001) - et al.
Vascular NK-1 receptor occurrence in normal and chronic painful Achilles and patellar tendons: studies on chemically unfixed as well as fixed specimens
Regul Pept
(2005) - et al.
In vivo microdialysis and immunohistochemical analyses of tendon tissue demonstrated high amounts of free glutamate and glutamate NMDAR1 receptors, but no signs of inflammation, in Jumper’s knee
J Orthop Res: Publ Orthop Res Soc
(2001) - et al.
Neurokinin 1-receptors and sensory neuropeptides in tendon insertions at the medial and lateral epicondyles of the humerus. Studies on tennis elbow and medial epicondylalgia
J Orthop Res
(2004) - et al.
Expression of neuropeptides and cytokines at the extensor carpi radialis brevis muscle origin
J Shoulder Elb Surg
(2002) - et al.
Posterior tibial tendon rupture: a refined classification system
Foot Ankle Clin
(2007) - et al.
Khan KM Abnormal tenocyte morphology is more prevalent than collagen disruption in asymptomatic athletes’ patellar tendons
J Orthop Res: Publ Orthop Res Soc
(2004) - et al.
Complement gene expression is regulated by pro-inflammatory cytokines and the anaphylatoxin C3a in human tenocytes
Mol Immunol
(2013) - et al.
Posterior tibial tendon dysfunction: clinical and magnetic resonance imaging findings having histology as reference standard
Eur J Radiol
(2018) - et al.
Tendon disorders of the foot and ankle, part 3: the posterior tibial tendon
Am J Sports Med
(2010)