Expression of growth factors, cytokines and matrix metalloproteinases in frozen shoulder

Abstract

F rozen shoulder is a chronic fibrosing condition of the capsule of the joint. The predominant cells involved are fibroblasts and myofibroblasts which lay down a dense matrix of type-I and type-III collagen within the capsule. This subsequently contracts leading to the typical features of pain and stiffness. Cytokines and growth factors regulate the growth and function of the fibroblasts of connective tissue and remodelling of the matrix is controlled by the matrix metalloproteinases (MMPs) and their inhibitors. Our aim was to determine whether there was an abnormal expression or secretion of cytokines, growth factors and MMPs in tissue samples from 14 patients with frozen shoulder using the reverse transcription/polymerase chain reaction (RT/PCR) technique and to compare the findings with those in tissue from four normal control shoulders and from five patients with Dupuytren's contracture. Tissue from frozen shoulders demonstrated the presence of mRNA for a large number of cytokines and growth factors although the frequency was only slightly higher than in the control tissue. The frequency for a positive signal for the proinflammatory cytokines Il-1 and TNF-and TNF-, was not as great as in the Dupuytren's tissue. The presence of mRNA for fibrogenic growth factors was, however, more similar to that obtained in the control and Dupuytren's tissue. This correlated with the histological findings which in most specimens showed a dense fibrous tissue response with few cells other than mature fibroblasts and with very little evidence of any active inflammatory cell process. Positive expressions of the mRNA for the MMPs were also increased, together with their natural inhibitor TIMP. The notable exception compared with control and Dupuytren's tissue was the absence of MMP-14, which is known to be a membrane-type MMP required for the activation of MMP-2 (gelatinase A). Understanding the control mechanisms which play a part in the pathogenesis of frozen shoulder may lead to the development of new regimes of treatment for this common, protracted and painful chronic fibrosing condition. The term 'frozen shoulder' was first used by Codman 1 who described the common features such as pain of gradual onset, which is felt near the insertion of the deltoid, inability to sleep on the affected side, painful restriction of elevation and external rotation and a normal radiological appearance. The disorder is characterised by dense fibrosis of the capsule of the shoulder, 2-4 in which the cellular element consists of fibroblasts and myofibroblasts, 5,6 leading to a contracture of the rotator interval and the coracohumeral ligament, which restricts movement. 7-9 Cytokines and other cellular growth factors are known to regulate the growth and function of fibroblasts in connective tissue. They are cell messengers derived from lymphoid cells, platelets, epithelial cells, endothelial cells, mesangial cells and fibroblasts and act in minute concentrations (nanomolar and femtomolar) by binding to cell receptors , causing a hormone-like acti...

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Association of MMP3 genotype with susceptibility to frozen shoulder: a case-control study in a Chinese Han population

“…A previous study showed that frozen shoulder can be induced by administration of synthetic TIMPs, suggesting that a decrease in the MMP/TIMP ratio affects collagen turnover (Hutchinson et al, 1998). Additionally, capsular tissues from frozen shoulder patients were found to show upregulated levels of MMP and natural TIMP mRNA (Bunker et al, 2000). Thus, limiting the amount and the function of MMPs may reduce connective tissue matrix degradation and thus limit synovial fibrosis progression.…”

“…Additionally, previous studies demonstrated that the elasticity of the joint capsule decreased in an adhesive capsulitis model and the range of motion became normal after capsular release (Hagiwara et al, 2006;Chimoto et al, 2007). Growth factors such as transforming growth factor-beta (TGF-b), platelet-derived growth factor, and hepatocyte growth factor are also involved in frozen shoulder (Rodeo et al, 1997;Bunker et al, 2000). Matrix metalloproteinases (MMPs) may play an important role in the pathogenesis of frozen shoulder (Bunker et al, 2000).…”

“…Growth factors such as transforming growth factor-beta (TGF-b), platelet-derived growth factor, and hepatocyte growth factor are also involved in frozen shoulder (Rodeo et al, 1997;Bunker et al, 2000). Matrix metalloproteinases (MMPs) may play an important role in the pathogenesis of frozen shoulder (Bunker et al, 2000). Genetic factors should may also be involved in frozen shoulder susceptibility and severity.…”