MMP-2 expression is associated with rapidly proliferative arteriosclerosis in the flexor tenosynovium and pain severity in carpal tunnel syndrome

Abstract

Due to the lack of correlation between symptom severity and electrophysiology or nerve function, the 'container hypothesis' has emerged as a new concept in carpal tunnel syndrome (CTS). This proposes that symptoms relate to connective tissue alteration rather than to nerve fibre pathology. This study was conducted to investigate the pathology of the flexor tenosynovium and its relationship with symptomatology. The subjects comprised 40 patients with electrophysiologically proven CTS who underwent open carpal tunnel release (age range: 31-79 years). In all patients, subjective symptom severity was assessed with a Likert scale and symptom duration was recorded preoperatively. Flexor tenosynovium biopsied during surgery was analysed for arterial and connective tissue alteration. Proliferative arteriosclerosis was graded using the modified Banff score. Gelatin zymography and immunohistochemistry were also performed to investigate the role of gelatinase in CTS. Relationships were evaluated using Spearman rank correlation coefficients. Proliferative arteriosclerosis occurred with disease progression in the flexor tenosynovium, in the absence of inflammation. This event did not correlate with patient age but correlated closely with symptom duration. Immunohistochemistry with antibodies against MMP-2 and elastic van Gieson staining revealed that arterioles express high levels of MMP-2 within 3 months of symptom onset and that intimal hyperplasia proceeded rapidly between 4 and 7 months, resulting in severe vascular narrowing. Gelatin zymography showed that MMP-2 activity correlated negatively with symptom duration and positively with pain severity.

Oxidative stress in subsynovial connective tissue of idiopathic carpal tunnel syndrome

“…35 In another pathologic study, the subjective symptoms were associated with MMP-2 activation and angiogenesis at the flexor tenosynovium. 2 Our study shows that a significant positive correlation exists between the subjective symptom severity of CTS and the immunoreactivities of eNOS and NF-␤, which suggests that oxidative stress in subsynovial connective tissues contributes to the subjective symptoms. CTS patients experience repetitive episode of pain, numbness, or tingling sensation, interspersed by symptom-free periods.…”

“…2,9,12 The typical pathologic findings in the tenosynovial tissue of idiopathic CTS are vascular proliferation, hypertrophy, and obstruction with wall thickening, which are similar to those seen in atherosclerosis. 12 Freeland et al 9 demonstrated that malondialdehyde levels (MDA; a marker of membrane lipid peroxidation) are elevated in serum and tenosynovium of CTS patients, and suggested that cellular damage created by neural and synovial ischemia induces cytokine production, and thus, the pathologic changes of idiopathic CTS.…”

“…Oxidative stress in subsynovial connective tissue triggers cytokine production in fibroblast and endothelial cells and causes vascular hypertrophy and subsequent tissue fibrosis. 2,8,9 The subjective symptoms of CTS are variable. They do not always depend on median nerve functional status or symptom durations and are not always reflected by findings from electrophysiological studies.…”

“…1,2 Previous studies demonstrated that no significant differences exist between patients with and without CTS in terms of transverse carpal ligament, 3,4 and, therefore, suggested that CTS is likely caused by an increase in carpal tunnel volume. This hypothesis is supported by recent MRI studies that showed evidence of tenosynovial swelling.…”

“…7 However, some authors pointed out that these pathological findings do not well correlate with the symptoms of CTS. 2,8 Freeland et al 9 suggested that ischemia-reperfusion injury is an important cause of idiopathic CTS. This injury type would increase the levels of several types of proinflammatory cytokines in tenosynovium, and possibly cause the pathologic changes observed in idiopathic CTS.…”