The relationship of VEGF and PGE₂ expression to extracellular matrix remodelling of the tenosynovium in the carpal tunnel syndrome

Abstract

Tenosynovial thickening within the confined space of the carpal tunnel is thought to be the cause of the carpal tunnel syndrome (CTS). However, little is known about the pathological mechanism of tenosynovial thickening. In this study, the role of prostaglandin E(2) (PGE(2)) and vascular endothelial growth factor (VEGF) (two representative molecules that can induce oedema by increasing vascular permeability) was analysed in CTS by using immunohistochemistry and enzyme-linked immunosorptive assay (ELISA). Expression of these molecules was compared with the patients' clinical histories and a temporary increase in production of these molecules was found in cells within the vessels and synovial lining during the intermediate phase of the syndrome when the histology of the tenosynovium changes from oedematous to fibrotic. Statistical analysis clearly demonstrated that there is a close correlation between the expression of PGE(2) and VEGF. Furthermore, immunohistochemical analysis with anti-proliferating cell nuclear antigen (PCNA) revealed that the area with distinct VEGF expression closely matched the area where endothelial cells, vascular smooth muscle cells, and synovial lining cells proliferate. In contrast, despite marked alteration in the extracellular matrix (ECM) component of the tenosynovium, the fibroblasts responsible for most ECM framework production do not proliferate during any phase of CTS. Histological analysis demonstrated that angiogenesis takes place only during the intermediate phase. Since clusters of capillaries and arterioles are often surrounded by type III collagen-rich, disorganized, degenerate connective tissue, which contains fewer fibroblasts than normal, angiogenesis appears to take place as a part of a regenerative reaction that results in fibrosis. These findings strongly indicate that both PGE(2) and VEGF are expressed in the tenosynovium in CTS during the intermediate phase and induce the histological changes seen in the tenosynovium.

Evaluation of the material properties of the subsynovial connective tissue in carpal tunnel syndrome

“…We have further shown that the SSCT of cadaver carpal tunnels fails in shear load at displacements which are well within the physiological range, and that the SSCT of CTS patients fails not only at higher loads, but also at lower displacements. We believe that this evidence supports the hypothesis, proposed by Lluch (1992) and others (Lluch, 1992,Tucci et al, 1997,Guimberteau, 2001,Sud et al, 2002,Ettema et al, 2004,Hirata et al, 2004,Hirata et al, 2005,Oh et al, 2006 that CTS is the result of the response of the SSCT to injury, possibly a shearing injury, with secondary pressure elevation within the carpal tunnel as a result of altered SSCT permeability. This hypothesis deserves further testing, preferably in an animal model where injury to the SSCT can be induced and its sequelae studied.…”

“…Recently, several immunohistological (Ettema et al, 2004,Oh et al, 2005 and biochemical studies ,Hirata et al, 2004,Hirata et al, 2005,Tsujii et al, 2006 have been reported describing the SSCT in carpal tunnel syndrome patients. The SSCT of CTS patients is fibrotic, with increased amounts of type III collagen, tenascin-C, versican, VEGF, PGE-2, MMP-2, IL-6, and TGF-beta, and decreased elastin.…”

Palmar bowing of the flexor retinaculum on wrist MRI correlates with subjective reports of pain in carpal tunnel syndrome

“…Histological studies have demonstrated that drastic connective tissue remodeling takes place in the flexor tenosynovium with progression of CTS, with various inflammatory mediators such as cytokines, prostaglandins, and proteases being involved in the process (7)(8)(9)(10)(11)(12)(13)(14)(15). Since the critical pathophysiology of CTS arises in the flexor tenosynovium, with the median nerve affected secondarily as a result of changes in the physical properties of the tenosynovium, magnetic resonance imaging (MRI), with its ability to detect soft-tissue abnormalities, has been suggested as an ideal diagnostic adjunct to evaluate the soft tissues within the carpal tunnel.…”

Enhanced expression of Wnt9a in the flexor tenosynovium in idiopathic carpal tunnel syndrome

“…23,24 Donato et al 6 also reported that ischemia not only induces VEGF-mediated angiogenesis but also stimulates fibroblast proliferation, suggesting that ischemia consequent to vascular stenosis may be a crucial factor associated with the occurrence of CTS. Regarding the relationship between nerves and VEGF expression in CTS, VEGF expression in the posterior interosseous nerve (PIN) was reported to be higher in subjects with diabetes relative to those without diabetes.…”