Immunolocalization of cytokines and their receptors in adhesive capsulitis of the shoulder

Abstract

The purpose of this study was to test the hypothesis that specific cytokines are involved in the initiation and evolution of the fibrotic process in adhesive capsulitis of the shoulder. After approval from the Institutional Review Board, biopsies of shoulder capsule and synovium were collected during shoulder arthroscopy from 19 patients with adhesive capsulitis, 14 patients with nonspecific synovitis and no fibrosis or clinical evidence of adhesive capsulitis, and seven patients undergoing surgery for another pathology who had a normal capsule and synovium. Immunohistochemical localization with monoclonal antibodies to transforming growth factor-beta and its receptor, platelet-derived growth factor and its receptor, basic fibroblast growth factor, interleukin-1 beta, tumor necrosis factor-alpha, and hepatocyte growth factor was performed using standard immunoperoxidase techniques. The frequency of cytokine staining was correlated with the clinical diagnosis. Synovial cells, fibroblasts, T-cells, and B-cells were identified with specific antibodies, and newly synthesized matrix was examined for type-I and type-III collagen by immunohistochemical staining. The predominant cell types present were synovial cells and fibroblasts. Staining for type-III collagen in adhesive capsulitis tissues indicated new deposition of collagen in the capsule. There was staining for transforming growth factor-beta and its receptor, platelet-derived growth factor and its receptor, interleukin-1 beta, and tumor necrosis factor-alpha in adhesive capsulitis and nonspecific synovitis tissues, compared with minimal staining in normal capsule. Staining was more frequent in synovial cells than in capsular cells. The frequency of cell and matrix staining for transforming growth factor-beta, platelet-derived growth factor, and hepatocyte growth factor was greater in adhesive capsulitis tissues than in those from patients with nonspecific synovitis. No difference in the frequency of staining between primary (idiopathic) and secondary adhesive capsulitis was found. The results of this study indicate that adhesive capsulitis involves both synovial hyperplasia and capsular fibrosis. Cytokines such as transforming growth factor-beta and platelet-derived growth factor may be involved in the inflammatory and fibrotic processes in adhesive capsulitis. Matrix-bound transforming growth factor-beta may act as a persistent stimulus, resulting in capsular fibrosis. Understanding the basic pathophysiology of adhesive capsulitis is an important step in the development of clinically useful antifibrotic agents that may serve as novel treatments for patients with this conditions.

Hyperthyroidism is a Risk Factor for Developing Adhesive Capsulitis of the Shoulder: A Nationwide Longitudinal Population-Based Study

“…The inflammatory process is considered another pathogenesis of adhesive capsulitis. Rodeo et al found elevated levels of pro-inflammatory cytokines in adhesive capsulitis patients14. They proposed that the stimulation of inflammation caused by cytokines can engender shoulder synovitis, and this can result in a fibrotic cascade that is associated with growth factors such as TGF-beta14.…”

“…Rodeo et al found elevated levels of pro-inflammatory cytokines in adhesive capsulitis patients14. They proposed that the stimulation of inflammation caused by cytokines can engender shoulder synovitis, and this can result in a fibrotic cascade that is associated with growth factors such as TGF-beta14. The chronic fibrosis process of capsulitis is confirmed by observing the histologic presentation of fibroblast cell proliferation.…”

Frozen Shoulder: Evidence and a Proposed Model Guiding Rehabilitation

“…Elevated cytokine levels appear predominately involved in the cellular mechanisms of sustained inflammation and fibrosis in primary and some secondary frozen shoulder. 19,49,75,101 Although the initial stimulus is unknown, Bunker et al 19 Frozen shoulder is typically considered an inflammatory process; however, this concept is being challenged. No significant inflammatory cells in the capsular tissue have been identified upon histological examination.…”

“…100 Although the precise etiology remains unclear, recent evidence identifies elevated serum cytokine levels as part of the process. 19,49,101 Cytokines and other growth factors facilitate tissue repair and remodeling as part of the inflammatory process. Elevated cytokine levels appear predominately involved in the cellular mechanisms of sustained inflammation and fibrosis in primary and some secondary frozen shoulder.…”

“…Elevated cytokine levels appear predominately involved in the cellular mechanisms of sustained inflammation and fibrosis in primary and some secondary frozen shoulder. 19,49,75,101 18,19,64,115 Numerous investigators report the visual presence of synovitis consistent with inflammation, 43,79,83,123 yet focal vascularity and synovial angiogenesis (increased papillary growth), rather than synovitis, are described by others. 18,50,124 In addition to confirmation of angiogenesis, frequent positive staining for nerve cells was found in patients with frozen shoulder.…”